Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institutes of Environmental Health Sciences (NIEHS), (http://www.niehs.nih.gov)

Title:  Engineered Nanomaterials: Linking Physical and Chemical Properties to Biology (U19)

Announcement Type
New

Request For Applications (RFA) Number: RFA-ES-09-011

Catalog of Federal Domestic Assistance Number(s)
93.113

Key Dates
Release Date: November 3, 2009
Letters of Intent Receipt Date: December 22, 2009
Application Receipt Date: January 22, 2010
Peer Review Date(s): May/June 2010
Council Review Date: August 2010
Earliest Anticipated Start Date: September 30, 2010 
Additional Information To Be Available Date (Url Activation Date): NA
Expiration Date: January 23, 2010

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• Purpose. The National Institute of Environmental Health Sciences invites applications that will (1) determine which physical or chemical characteristic of an engineered nanomaterial (ENM), or cluster of characteristics, is integral to ENM-molecular interactions in a cellular process or organ system and (2) relate these findings to potential health effects. NIEHS recognizes that three types of activities need to converge to accomplish this research agenda. The first activity should focus on a detailed understanding of how physical and chemical characteristics of ENMs influence their molecular interactions at the cellular level, while the second activity should determine how the physical and chemical characteristics critical to that interaction are associated with any observed physiological or pathobiological events. The third activity will capitalize on these multidisciplinary efforts through integration of biochemical, molecular, and physiological mechanisms to expand traditional hazard identification and health risk assessment. An extraordinary level of synergy, integration, and potential for advancement of ENM hazard identification and risk assessment is expected.
• Proposals responsive to this FOA should employ three projects that will examine an overarching research theme through mechanistic studies and in vitro, ex vivo, and in vivo model systems. Grants awarded under this FOA will become part of a consortium that will collaboratively manage the research conducted through the individual grants.
• Mechanism of Support. This FOA will utilize the U19 grant mechanism
• Funds Available and Anticipated Number of Awards.  The total amount of funding to be committed to this program is $5 million (total costs) per year for 5 years.
• Budget and Project Period.  An applicant may request a project period of up to 5 years and a budget for direct costs up to $750,000 dollars per year.
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application.
• Number of Applications.  Applicants may submit only one application.
• Resubmissions.  Resubmission applications are not permitted in response to this FOA.
• Renewals.  Renewal applications are not permitted in response to this FOA.  
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates
• Application Materials. See Section IV.1 for application materials.
• Hearing Impaired.  Telecommunications for the hearing impaired are available at: TTY: (301) 451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Receipt, Review and Anticipated Start Dates
         1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
   D.  Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
         1. Principal Investigator Rights and Responsibilities
         2. NIH Responsibilities
         3. Collaborative Responsibilities
         4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Nature of the Research Opportunity

The objective of this program is to understand how physical and chemical characteristics of engineered nanomaterials (ENMs) influence their molecular interactions with biological matrices and elicit biological responses. The awards made through this FOA will use a multi-project cooperative agreement (U19) mechanism.  Each application must include an overarching research focus that integrates physical and chemical characteristics of ENMs with biological processes.  Three research projects will define this experimental paradigm.  (1) The investigators will determine the physical and chemical characteristics of ENMs that dictate biological interactions at the molecular and cellular levels.  These responses include interactions with macromolecules, intracellular translocation/sequestration, transport mechanisms, and defined signaling cascades.  (2) In parallel with these in vitro studies, the investigators will examine the specific physical and chemical characteristics of ENMs that dictate in vivo responses such as absorption, distribution, metabolism and elimination (ADME) as well as physiological and pathobiological events in target and secondary organs, using appropriate routes of exposure and dose metrics. (3) The final research activity will develop and apply methods and mode of action approaches to integrate information at the biochemical, molecular, cellular, and organism level (such as those from Projects 1 and 2) into traditional risk assessment paradigms. This third project will be supported initially as a two year independent developmental activity. It will be followed by potential support through a collaborative effort across all of the funded grants. This follow-on collaborative effort will extend the mechanistic and physiological understanding gained from Projects 1 and 2 to development of relevant metrics for expanded hazard characterization and risk assessment of ENM.

This solicitation represents one of the major NIEHS initiatives to support goals identified in the National Nanotechnology Initiative, Strategy for Nanotechnology-related Environment, Health, and Safety (EHS) Research.  This program extends NIEHS interests and investments in engineered nanomaterial EHS research activities. that were initiated in 2004 by participating in an interagency FOA with NSF, NIOSH and US EPA and with a second FOA in 2007 partnering with other NIH ICs, NIOSH and US EPA. NIEHS further identified nanomaterial EHS as a high priority research area by designating nanomaterial safety as one of its high priority areas for the ARRA Grand Opportunity (GO) Grant program, as well as selecting this as one of its topic areas for the ARRA Challenge Grant program. 

Background

ENMs represent a significant breakthrough in material design and development for medicine, industry, and consumer products. Global demand for nanomaterials and nano-enabled devices will approach $3.1 trillion by 2015. This increased production provides increased opportunities for exposures with unknown health consequences. The novel size and size-dependent physical and chemical properties that make ENMs useful also make their interactions with biological systems difficult to anticipate and critically important to explore. ENMs can be generated with relative ease and are currently used in diverse industrial applications from electronics, pharmaceuticals, biomedicine, and cosmetics to environmental remediation. The unique properties stemming from their small dimensions, such as high reactivity, large surface area, and tunable nature of their optical, electrical and magnetic properties, differentiate them from their micro- and meso-scale counterparts. Moreover, these unique physical and chemical properties are determined by variation in size and shape as well as chemical composition.  The range of ENMs with different physical and chemical properties in use and with potential for human exposure is vast. 

Many studies on ENM interaction with biological systems are ongoing, however significant additional information is critical to assess potential health risks from exposure. Furthermore, most published research on these interactions does not provide detailed physical and chemical characterization of the nanomaterials and does not identify which of the material’s characteristics are critical to the biology. Therefore, the effect of subtle changes in the physical and chemical properties of an ENM (i.e., surface chemistry, size, or charge) on the entry of ENMs into cells or exposure organs, their absorption, transport or sequestration, and the resulting sequence of biological events are largely unknown. Information on initial responses at the target cell/tissue level, taken together with an understanding of intracellular mechanisms and organism responses will provide integrated knowledge to better understand and predict the health effects of exposure to ENMs.

Multiple characteristics of ENMs contribute to the determination of their safety parameters.  Indeed, the unique physical and chemical properties of ENMs present several major challenges when assessing the risk. Traditional risk assessment approaches are based on dose-response research that relates biological effect to mass or chemical concentration.  Because nanomaterials behave as particles, mass and concentration may not be the appropriate measures of dose, whether utilizing in vitro or in vivo models.  Size, shape, particle number, agglomeration state, surface chemistry, reactivity, and surface area are thought to be critical parameters of ENM dose and are, therefore, factors in understanding the ENM dose-response relationship.  Consequently, expanded or new risk assessment models are needed that incorporate these critical factors with mechanistic and systems-level effects. This characteristics-based effects research may also be generalizable and allow prediction of behavior for other ENMs. 

Knowledge of the specific physical or chemical properties of ENMs that dictate interaction with biological systems is critical not only for informing sound scientific bases for regulatory decision processes, but also for the responsible development of a new generation of ENMs. 

Scope of Research

Each applicant will develop an overarching theme to address the potential health implications of ENMs and will craft an interdisciplinary research approach that incorporates a basic mechanistic understanding of ENM-biological interactions as dictated by the physical and chemical characteristic of ENMs.

The general characteristics of each grant application must include:

• A central overarching theme that develops approaches to evaluate, understand, and predict toxicity mechanisms and potential health implications of exposure to ENMs.
• Collaborative, integrated research projects to understand basic ENM-molecular interactions at cellular, tissue, and organ system levels. Diverse routes of exposure and model systems to predict biological response based on specific physical and chemical characteristics of ENMs should be employed.
• A research plan to facilitate the extension of the knowledge gained from these efforts (biochemical, molecular and physiological endpoints) to inform ENM hazard identification, risk assessment, and risk characterization. This activity must be carried out in collaboration with risk assessment researchers who have demonstrated an understanding of toxicity testing in the regulatory context.

Scientific Knowledge to be Achieved

The goal of this initiative is to gain a basic understanding of how variation in chemical composition and structural arrangement of ENMs dictate biological interaction with macromolecules, sub-cellular organelles, cellular or organ systems and ultimately affect physiological function. This highly specific, mechanistic understanding of ENM-biological interaction will provide a sound scientific basis for the development, characterization, and interpretation of ENM hazard and risk assessment strategies. Ultimately the knowledge gained from these efforts is expected to accelerate (1) characterization of potential health implications, if any are associated with exposure to ENMs, and (2) contribute significantly to the knowledge base that will minimize risk and maximize benefit in design of the next generation of ENMs.

Objectives of the Research Program

In order to understand the risks to human health associated with ENMs that are in commercial use and provide the potential for human exposure, it is critical to understand fundamental determinants of the interaction between a nanomaterial and biological systems and how these interactions are governed by the specific physical and chemical properties of the ENM. The research program funded under this solicitation is expected to accelerate the application of knowledge to the development of ENMs with minimal adverse biological consequences.

Types of Research and Experimental Approaches to be Used

Each Principal Investigator will craft an interdisciplinary program that uses a biologically-based paradigm to understand the influence of specific physical and chemical characteristics of ENMs on both molecular and physiological endpoints. The biological processes include, but are not limited to, mechanistic endpoints such as cell cycling, vesicular trafficking, transcription, signal transduction and metabolism, physiological endpoints including uptake, adsorption, transport, sequestration, and elimination of ENMs as well as organ and organism function.

Research conducted as part of these multi-project programs could include investigators with demonstrated expertise in materials science, physics, chemistry, engineering, cell and molecular biology, toxicology, exposure science, and risk assessment.  In addition to the effort being conducted by the grantees of this program, the NIEHS will provide contractual support to the grantees including:

• ENM characterization:  Because physical and chemical characterization of ENM is critical to the success of this research, ENM characterization will be accomplished two ways. Each Principal Investigator must characterize in house a minimum set of ENM physical and chemical parameters for the materials chosen for their projects. In addition, all grantees will be required to send an aliquot of their ENMs to a centralized characterization facility for a second detailed characterization of the ENM without additional cost to the PI. The services provided by this group will include, but are not limited to physical properties, including the particle’s size, size distribution, molecular weight, density, surface area, porosity, hydrophilicity/hydrophobicity, surface charge density, purity, sterility, surface chemistry, and stability.
• Informatics: To facilitate the dissemination of findings of this initiative and provide maximum impact to the field, the NIH will provide direct access to a database for inclusion of both material’s characterization and biological data. All applicants are expected to include a plan for sharing research data in their application.
• See section III Other Submission Requirements for details.

To advance our goals of understanding more precisely the physical and chemical properties that determine biological interactions,  investigators may choose to (1) thoroughly investigate the effect of a single physical and chemical parameter, (2) use hypothesis-driven approaches to investigate the pair-wise effect of two physical and chemical characteristics or (3) use statistically valid global approaches to identify higher order interactions. 

Project 1:  Research in the first project must be designed to understand mechanistic effects of variations in specific physical and chemical properties using ex vivo and/or in vitro investigations. The investigators should define a focus relating material characterization to the mechanisms of biological response.  Relevant examples include, but are not limited to:

• Interaction of ENMs with macromolecules, membranes, and organelles. For example, how alterations in:
  • surface chemistry dictates ENM-protein interactions and downstream protein-protein interactions.
  • size dictates ENM-lipid interactions and downstream signaling events.
  • surface charge distribution alters mitochondrial function
• Influence of ENMs on cellular processes. For example, how ENM:
  • shape dictates transport across plasma membrane.
  • agglomeration influences sub-cellular localization and sequestration
  • surface reactivity influences homeostatic mechanisms
• Multivariate analysis to identify the physical and chemical characteristics of ENMs that influence a biological function.
• Influence of nanomaterials on signal transduction systems and downstream effects, including immune signaling, inflammation, apoptosis/necrosis, or genotoxicity/carcinogenicity.
• Comparison of cell-type specific biological response patterns at the cellular or molecular scale for ENMs of similar class, size, surface area, functional group, etc.
• Comparison of patterns of biological response at the cellular or molecular scale across species, including humans, and the relationship of those patterns to ENM physical and chemical properties.

Project 2: Research in the second project must be designed to understand physiological and pathobiological effects of specific physical and chemical properties of ENMs at the organ and organism level using acute or sub-chronic in vivo exposures (using relevant routes and doses), isolated organs, and/or well validated computational models. An experimental approach may utilize genetically manipulated mouse strains and disease susceptible models to understand and extrapolate potential health implications to susceptible/vulnerable human populations.

Relevant examples include, but are not limited to:

• The physical and chemical properties of an ENM that drive its pharmacokinetics, including characterization of absorption through different routes of exposure, organ distribution, metabolism, and elimination.
• Influence of ENMs on physiological functions. For example, how alterations in ENM: 
  • size and size distribution affect pulmonary function following inhalational exposure to ENMs.
  • surface area dictates a target organ-specific inflammatory response.
  • surface charge distribution influences trans-placental transport.
  • Influence of ENMs on pathological processes. For example, how ENM:
  • shape dictates cell-specific hyperplastic lesions in target organs.
  • hydrophobicity influences pulmonary fibrosis
  • surface reactivity influences gene expression profiles in inflammation/fibrotic phenotype

Project 3:  The research in this project will develop approaches to translate the knowledge of the in vitro and in vivo effects of ENM into a risk assessment paradigm or to expand the risk assessment methods used to characterize ENM safety.

This effort will begin as a two-year developmental activity (similar in scope and concept to an R21 exploratory/developmental research project). Relevant examples of possible research foci for the first two years of Project 3 include:

• Develop or improve methods for adapting traditional Risk assessment parameters such as NOAEL, LOAEL, etc, to ENM.
• Develop predictive models of risk based on the physicochemical characteristics of ENM.
• Develop computational methods to integrate information at multiple scales such as molecular, cellular, organ and organism.
• Develop novel extrapolation models to predict human health risks based on animal toxicology data including potential susceptibility issues
• Develop methods to incorporate material variability and to extrapolate from isolated ENMs to commercial products.
• Assess the adequacy of current test methods and pharmacokinetic models to determine additional data streams necessary for improved risk assessment.

During the third through fifth years of the effort, it is anticipated that Project 3 will continue as a collaborative effort across the consortium and will focus on integrating the results from Projects 1 and 2 into an expanded risk assessment model.  This effort will identify potential new endpoints for ENM risk assessment and may involve the use of a common ENM, or set of ENMs, chosen by the steering committee. While the direction of the research in this phase of Project 3 will be determined by the Steering Committee, research may include:

• The use of in vitro and in vivo data to define ‘hazard’ based on, for instance, mechanisms of action across species, or the mechanism of response across diverse ENMs.
• The use of physiologically-based pharmacokinetic models to relate the relationship between the  physical and chemical properties of ENM to biopersistence and bioaccumulation.
• Examination of the adequacy of available methods to quantitatively extrapolate from the exposures used in animal toxicology studies (inhalation, instillation, oral, dermal, and in vitro) to human exposure and health effects characterization.
• Development of novel extrapolation models to predict human health risks based on animal toxicology data including potential susceptibility issues.
• Creation of new methods to incorporate material variability and the associated health risks of ENMs into commercial product development.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1.Mechanism of Support

This funding opportunity will use the U19 award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses “Just-in-Time” information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). 

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The total amount of funding committed to this program is $5 million (total costs) per year over a 5-year period to fund 4-5 new grants in response to this FOA. An applicant may request a project period of up to 5 years and a budget for direct costs up to $750,000 dollars per year.

The estimated amount of funds available for support of 4-5 projects awarded as a result of this announcement is $5 million for fiscal year 2010. Future year amounts will depend on annual appropriations.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education
• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribally Designated Organizations
• County Governments
• City or Township Governments
• Special District Governments
• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• U.S. Territory or Possession
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)
• Other(s):
  • Eligible Agencies of the Federal Government
  • Faith-based or Community-based Organizations.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

In order to be considered eligible for this FOA, the U19 Centers must have exactly three research projects, must include an Administrative Core, a scientific core (see below), and a Milestones section (see below). Each application should require a scientific core with capabilities to generate, characterize ENMs. The lead for the core should demonstrate expertise in ENMs synthesis, chemistry and physical and chemical characterization.  If the application contains fewer than the required three research projects or does not have substantial and significant merit, the application will not be recommended for further consideration.

An institution may submit only one application; however, applications may include investigators from more than one institution if such arrangements enhance the scientific strength of the proposed research program.  In addition, a PD/PI on one application may also serve as a Project Leader and/or Scientific Core Leader on another multi-project application if there is no scientific overlap between the applications.

The PD/PI is requested to commit substantial time and effort to ensure success of the Program.  It is required that the PD/PI devotes a minimum of 1.8 months effort, and that the Project Leaders and Core Leaders devote a minimum of 1.8 months effort.  The level of effort is expected to be commensurate with the direct involvement necessary to ensure successful implementation and management of the Program.

Milestones

All applications must include a specific section labeled “Milestones” for each year. Milestones should be annual, well-described, quantitative, and scientifically justified and not simply a restatement of the specific aims. Rather, the milestones should offer a timeline and a research goal. These milestones will be used to judge the success of the proposed research on an individual-project basis. It is expected that the milestones will be adjusted annually at the award anniversary dates to incorporate the group's scientific accomplishments and progress and to reflect any recommendations of the Steering and Advisory Committees.

Meetings

The U19 investigators will be expected to attend Steering Committee meetings two times per year and participate in conference calls once in three months to discuss their research progress.  Funds to support travel of the key investigators to attend these meetings should be included in the application budget.  

Number of Applications. Applicants may submit only one application.

Resubmissions.  Resubmission applications are not permitted in response to this FOA. 

Renewals.  Renewal applications are not permitted in response to this FOA. 

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

Foreign Organizations (Non-domestic (non-U.S.) Entity)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from foreign organizations must:

• Request budgets in U.S. dollars.
• Contain detailed budgets. See NOT-OD-06-096.

In addition, for applications from foreign organizations:

• Charge back of customs and import fees is not allowed.
• Every effort should be made to comply with the format specifications, which are based upon a standard U.S. paper size of 8.5” x 11” within each PDF.
• Funds for up to 8% Facilities and Administrative (F&A) costs (excluding equipment) may be requested. See NOT-OD-01-028, March 29, 2001.                        
• Organizations must comply with Federal/NIH policies on human subjects, animals, and biohazards.
• Organizations must comply with Federal/NIH biosafety and biosecurity regulations. See Section VI.2., “Administrative and National Policy Requirements”

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs 

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a – 3h for all PD/PIs. NIH requires one PD/PI be designated as the “contact PD/PI” for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the “Contact PD/PI, et. al.” The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the Research Plan, entitled “Multiple PD/PI Leadership Plan” must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letter of Intent Receipt Date: December 22, 2009
Application Receipt Date:  January 22, 2010
Peer Review Date(s):  May/June 2010
Council Review Date:  August 2010
Earliest Anticipated Start Date: September 30, 2010

3.A.1. Letter of Intent

A letter of intent is not required for the funding opportunity.

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Sally Eckert-Tilotta, PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences 
111 T.W. Alexander Drive
PO Box 12233, Mail Drop K3-03
Research Triangle Park,  NC 27709
Telephone: 919-541-1446
FAX: 919-316-4606
Email: eckertt1@niehs.nih.gov

Please note that email submission of letter of intent is preferred.

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Sally Eckert-Tilotta, PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences 
111 T.W. Alexander Drive
PO Box 12233, Mail Drop K3-03
Research Triangle Park,  NC 27709
Telephone: 919-541-1446
FAX: 919-316-4606
Email: eckertt1@niehs.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed.  Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute. Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

The U19 investigators will be expected to attend Steering Committee meetings two times per year and participate in monthly conference calls to discuss their research progress.  Funds to support travel of the key investigators to attend these meetings should be included in the application budget.

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Do not use the Appendix to circumvent the page limitations. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: As this research program involves collaborative research efforts through consortium, the grantees will be expected to participate actively and openly in semi-annual meetings. Substantial information sharing is critical to the program, so how an applicant plans to achieve this would be considered as a term and condition of the award; failure to openly share information will be considered in continued funding consistent with achieving the goals of the program. Also, the grantees will be expected to deposit data on physical and chemical characteristics of the ENMs and biological endpoints data as appropriate to an NIH database site available to the grantees. Details on the required format and software details will be provided to the grantees in the first face to face meeting immediately on award. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the scientific discovery or in some cases jeopardizing the protection of human subjects. Applicants should describe their plans for participating in the grantee meetings and for managing any appropriate intellectual property concerns in the context of those meetings and other opportunities for information sharing in the Other Research Plan Sections under Resource Sharing Plan(s) attachments section. Applicants should budget for travel funds for the PD/PI and one additional lead investigator to attend the annual meeting.

IApplicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible.  A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition.  For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Specific Instructions for Foreign Applications

All foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096, August 23, 2006.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Review Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIEHS and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned an impact/priority score.
• Receive a written critique.
• Receive a second level of review by the National Advisory Environmental Health Sciences Council.

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability.  As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system. 

Overall Impact: Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Due to the integrated and coordinated research effort required for the proposed research the review criteria described below will be considered for the overall application, as well as for individual research projects.

Significance: Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

• Will the program as a whole contribute to the knowledge of potential links between characteristics of nanomaterials and biological response or health effects of exposure to nanomaterials?
• Does the overarching theme of the program contribute to scientific knowledge appropriate to the development of human health effects assessment and risk characterization for ENMs? 
• Will combining the component projects into a multi-project program result in scientific knowledge beyond that which is achievable if each project were to be pursued independently?

Projects 1 and 2:

• Will the project advance understanding of the influence of the physical and chemical characteristics of ENMs on the mechanistic (Project 1) or physiological (Project 2) responses at cellular and organ system levels?

Research Project 3:

• Will the project advance understanding of an integrated assessment of toxicity, health effects and risk of human exposure to nanomaterials?
• Will the project lend itself to a contribution to a later consortium effort dedicated to addressing the health effects risk characterization and assessment of exposure to nanomaterials?

Investigators: Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

• Do the PD/PI, program director, or leadership team possess the leadership skills and scientific ability to develop a program of integrated research projects with a well-defined central research focus?

Projects 1 and 2:

• Is the commitment of the Project Leader to the project adequate to ensure success of the project? 

Project 3:

• Is the commitment of the Project Leader adequate to ensure success? 

Innovation: Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach: Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

• Are the projects and cores, as well as the integration, designed to contribute to an overarching theme?
• Do the projects address the critical elements of nanomaterial characteristics, mechanistic and biological response, and health effects assessment?
• Are the projects likely to produce data that can be translated into a risk assessment paradigm?

Projects 1 and 2:

·         Are there a sound scientific rationale and basis for the proposed approach/strategy, and does the strength of the existing data support feasibility and potential success?

• Is the proposed project appropriate for the stage of knowledge in the field?
• Are the studies designed to maximize potential for success?
• How do the expected outcomes relate to the objectives of the project, and to the overall program?

Project 3:

• If successful, how well will project goals contribute to a broader effort for hazard identification, prioritization and risk characterization?

Environment: Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Scientific Cores

• Are the justification and usefulness of the core facilities to the individual research projects appropriate and sound?
• Is there a strong relationship of the core to the central focus of the overall program?
• Are the quality of the procedures, techniques, quality control, and criteria for prioritization and usage appropriate to adequately support the use of the core?
• Are the qualifications, competence, and commitment of the Scientific Core Leader and key personnel appropriate to provide quality services?

Administrative Core

• Is there a decision-making process for the management of funds and resources?  Is there evidence of an ability to provide administrative support to the project and core leaders?
• Does the program’s internal plan promote coordination among research projects and cores?
• Does the senior leadership have appropriate experience and have they demonstrated effective and responsible leadership in the past?  Is the level of effort requested adequate?
• Are the qualifications, duties and time commitments of administrative staff appropriate to contribute to the needs and conduct of the program’s research activities?
• Are the resources committed to the Administrative Core adequate?

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protections for Human Subjects.  For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects  and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Inclusion of Women, Minorities, and Children.  When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals.  The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

Biohazards.  Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Additional Review Considerations

As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.

Budget and Period Support.  Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Select Agents Research. Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Applications from Foreign Organizations.  Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Resource Sharing Plans.  Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable:  1) Data Sharing Plan (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html

Selection Process

The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of the proposed project to program priorities

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2. A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the details for the project within the guidelines of RFA-09-011 and for performing the scientific activities. The PI will agree to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities".

The PI will be expected to:

• Participate in the Steering Committee and regular conference calls.
• Share results according to the data release policy developed for and by this project.
• Participate in Steering Committee and consortium activities, including attending regularly scheduled conference calls, two meetings annually to discuss the project's progress and coordinating the publication of research results.
• Fully disclose all database schema, algorithms, software source code, and methods to the other members of the Consortium for purposes of scientific evaluation.
• Not disclose confidential information obtained from other members of the program.
• Adhere to NIH policies regarding intellectual property and other policies that might be established during the course of this activity.
• Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Advisory Committee.
• Accept and implement the common guidelines and procedures approved by the Steering Committee,.
• Each PI is voting member of the Steering Committee and is required to attend the twice-yearly Steering Committee meetings. NIEHS program staff has one vote.
• Determine experimental approaches, design protocols, set project milestones, and conduct experiments.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2. A.2. NIH Responsibilities

The Project Scientists are NIH extramural staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of the Project Scientists will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the Steering Committee and that the NIH Project Scientists will be given the opportunity to offer input to this process. The Project Scientists will have the following substantial involvement:

• Participate with the other Steering Committee members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted.
• Assist and facilitate the group process and not direct it.
• Negotiate milestones, e.g., throughput, quality, and cost, with the awardees as necessary.
• Serve as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NIH. The Project Scientists will also coordinate the efforts of groups participating in the Consortium.
• Attend all Steering Committee meetings as non-voting members and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Project Scientists must be informed of all major interactions of members of the Steering Committee. The NIH Project Scientists will be responsible for scheduling the time and preparing concise minutes or summaries of the Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting.
• Review periodically the progress of the projects.
• Provide relevant expertise and overall knowledge of NIH-sponsored research to facilitate annual workshops with researchers in the international community who are engaged in ENMs health implications research.
• Serve on subcommittees of the Steering Committee, as appropriate.
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Provide advice in the management and technical performance of the research.
• Assist in promoting the availability of other NIH resources developed in the course of this project to the scientific community at large.
• Participate in data analyses, interpretations and, where warranted, co-authorship of the publication of results of research conducted through the Consortium.

Additionally, an NIEHS Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.3. Collaborative Responsibilities 

Management and Governance

All involved investigators of the Program will meet two times a year in order to share information and assess progress. The Steering Committee will serve as the main coordinating body of the Consortium. The Steering Committee members will meet annually with researchers in the international community who are engaged in ENMs health implications research to harmonize NIH-funded research efforts with private and international efforts and to avoid overlap and maximize synergy. The Steering Committee may add additional members. Other government staff may attend the Steering Committee meetings if their expertise is required for specific discussions.

The Steering Committee will be responsible for coordinating the activities being conducted by the Consortium. To address particular issues, the Steering Committee may establish working groups as needed.

Consortium Steering Committee

The Consortium Steering Committee will consist of Principal Investigators of each grant awarded in this program, and NIH Staff and the chairperson will be selected by the Government and serve one-year terms. The Steering Committee will serve as the main governing board of the Consortium established under this RFA. The committee will meet by regularly scheduled teleconference and bi-annually in person. The Steering Committee will be responsible for making scientific and administrative recommendations to the NIEHS.

The Steering Committee will be responsible for coordinating the activities being conducted by the Consortium. To address particular issues, the Steering Committee may establish working groups as needed, which may include representatives from the Consortium, and the NIH and possibly other experts. Such groups might include ones to: 1) address data management issues; 3) analyze the project data; 4) develop quality standards and methods to assess data quality; and 5) handle communication issues and develop principles for reporting findings. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4.Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Srikanth Nadadur, Ph.D
Division of Extramural Research and Training
National Institute of Environmental Health Sciences 
111 T.W. Alexander Drive
PO Box 12233, Mail Drop K3-15
Research Triangle Park,  NC 27709
Telephone: 919-541-5327
FAX: 919-541-3289
Email: nadadurs@niehs.nih.gov

2. Peer Review Contacts:

Sally Eckert-Tilotta, Ph.D
Division of Extramural Research and Training
National Institute of Environmental Health Sciences 
111 T.W. Alexander Drive
PO Box 12233, Mail Drop K3-03
Research Triangle Park,  NC 27709
Telephone: 919-541-1446
FAX: 919-316-4606
Email: eckertt1@niehs.nih.gov

3. Financial or Grants Management Contacts:

Dorothy Duke
National Institute of Environmental Health Sciences 
111 T.W. Alexander Drive
PO Box 12233, Mail Drop K3-11
Research Triangle Park,  NC 27709
Telephone: 919-541-2749
FAX: 919-541-2860
Email: duke3@niehs.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award.  For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.