THE ROLE OF INNATE IMMUNITY IN AUTOIMMUNE RHEUMATIC DISEASES RELEASE DATE: September 24, 2003 RFA Number: RFA-AR-04-003 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (http://www.niams.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.846 LETTER OF INTENT RECEIPT DATE: November 19, 2003 APPLICATION RECEIPT DATE: December 19, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Arthritis and Musculoskeletal and Skin Diseases invites grant applications for research to advance our understanding of the role of the innate immune system in the etiopathogenesis of autoimmune rheumatic diseases. Autoreactive B and T cells have been the traditional focus of autoimmune research. Rather than act separately and sequentially, it has become apparent that an interplay between the innate immune system and the adaptive immune system results in either the adaptive immune response or the autoimmune response. Advances have been made in understanding the basic immunology of innate immunity and its interaction with adaptive immunity. The purpose of this RFA is to stimulate and encourage innovative and multidisciplinary research to translate this knowledge of innate immunity into an understanding of its role in the etiopathogenesis of autoimmune rheumatic diseases. The applications in response to this RFA may be for individual research projects (R01) or for exploratory/developmental grants (R21). RESEARCH OBJECTIVES Although apparently separate, the innate and adaptive immune systems are in a delicate balance with constant interaction. The innate immune system which is nonspecific with rapid response kinetics but lacks memory, includes: effector cells (natural killer cells, gamma delta T cells, plasmacytoid dendritic cells, macrophages, neutrophils), cellular receptors (Fc receptors, Complement receptors, Scavenger receptors, Toll Receptors), effector proteins (complement, mannose binding lectin C-reactive protein, coagulation factors), and cytokines (TNF, Interleukin (IL)-1, Interferon (IFN)-gamma, IFN alpha and beta, IL-15 etc.). On the other hand, adaptive immunity is specific with slow response kinetics and has memory and is primarily T and B cells and dendritic cells. Autoimmune rheumatic diseases become apparent when there is measurable end-organ damage, characterized by the presence of autoantibodies produced by self-reactive B cells and/or the attack on self-tissues by self-reactive T cells. The generation and/or persistence of these autoreactive cells may be due to the dysfunction of regulatory pathways of the innate immune system. For example, specific gene-targeted mutations in mice result in defects in proteins of the innate immune system and an apparent failure in clearance of apoptotic cells and/or nuclear debris. These animals develop a lupus-like syndrome characterized by autoantibodies to double-stranded DNA or nuclear components. Deficiency in mannose-binding lectin correlates with earlier development and increased severity of rheumatoid arthritis in humans. These studies suggest that innate immunity plays a protective role in maintaining self-tolerance. However, innate immunity may also play a role in autoimmune disease pathogenesis. Onset and severity of collagen-induced arthritis (CiA) is inhibited in mice that are deficient in the complement component, C5, and CiA can also be inhibited by antibodies to C5. In addition, Toll-like Receptors (TLRs) on autoreactive B cells may be involved in the generation of rheumatoid factors. Finally, evidence that TLRs expressed on antigen-presenting cells can elicit differential cytokine secretion skews the CD4 T cell response, and suggests that conditions and timing may direct whether the promoting or the protecting nature of the innate immune system is elicited. The purpose of this solicitation is to encourage research to increase our understanding of the role of innate immunity in the etiopathogenesis of autoimmune rheumatic diseases. Understanding the role of the innate immune system in the earlier events of the etiopathogenesis of autoimmune diseases could lead to prevention of end organ damage and earlier intervention in autoimmune rheumatic diseases. Further analysis and identification of innate immunity involvement during the progression of the disease may lead to intervention and disease attenuation, thus decreasing morbidity and improving quality of life. Relevant autoimmune rheumatic diseases covered under this RFA include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, scleroderma and spondyloarthropathies in adults and children. Collaborations or research teams combining interdisciplinary approaches between autoimmune disease researchers and experts in other related scientific fields are highly encouraged. Epidemiological and clinical treatment projects are beyond the scope of this RFA. Appropriate research areas may include, but are not limited to the following: o development and evaluation of new experimental systems, including the generation of transgenic and other genetically engineered animal models to study cellular, molecular and genetic aspects of innate immunity in rheumatic diseases o studies to identify molecular and cellular pathways of innate immunity that enable initiation, maintenance and/or perpetuation of rheumatic disease manifestations o examination and characterization of the interactive pathways between innate and adaptive immunity that lead to rheumatic diseases o development of approaches that inhibit the interactive pathways between innate and adaptive immunity that lead to rheumatic diseases o immediate and long term effects of pharmacological and other interventions that inhibit innate immunity in rheumatic diseases o research correlating clinical findings with markers of the innate immune response in rheumatic diseases MECHANISM OF SUPPORT This RFA will use the NIH R01 (investigator-initiated research project grant) and the R21 (exploratory/developmental research project) award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also the uses the modular budgeting format. (See https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. R01 Applications: The R01 application may request a project period of up to four years and a budget for direct costs of up to $250,000 per year. R21 Applications: The R21 application may request a project period of up to two years with a budget for direct costs not to exceed $100,000 per year, not including indirect costs for collaborating institutions, if any. The R21 projects solicited under this RFA are exploratory/developmental grants. In the context of this RFA, exploratory/developmental grants are to be used to either a) gather preliminary data to develop a research basis for a subsequent application through other mechanisms, i.e. R01, P01, or b) to explore the feasibility of an innovative or conceptually creative research question or approach that may not be justifiable through existing research to compete as a standard research project grant (R01). Because innovative projects may require a preliminary test of feasibility, the R21 mechanism could provide short- term support for such preliminary work. Exploratory/developmental studies may not be used for large-scale undertakings, or to support or supplement ongoing research. FUNDS AVAILABLE NIAMS intends to commit approximately $1,500,000 in FY 2004 to fund four to eight new grants in response to this RFA. 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 NIAMS provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local Governments o Eligible agencies of the Federal Government o Domestic or foreign institutions/organizations o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their 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 programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: o Direct your questions about scientific/research issues to: Elizabeth Gretz, Ph.D. Director, Immunology and Inflammation Extramural Program Rheumatic Diseases Branch, NIAMS, NIH, DHHS One Democracy Plaza 6701 Democracy Boulevard, Suite 800, MSC 4872 Bethesda, MD 20892-4872 Telephone: (301) 594-5032 FAX: (301) 480-4543 Email: gretze@mail.nih.gov o Direct your questions about peer review issues to: Teresa Nesbitt, D.V.M., Ph.D. Chief, Review Branch, NIAMS, NIH, DHHS One Democracy Plaza 6701 Democracy Boulevard, Suite 800, MSC 4872 Bethesda, MD 20892-4872 Telephone: (301) 594-4953 FAX: (301) 480-4543 Email: nesbittt@mail.nih.gov o Direct your questions about financial or grants management matters to: Michael Morse Deputy Chief, Grants Management Branch, NIAMS, NIH, DHHS One Democracy Plaza 6701 Democracy Boulevard, Suite 800, MSC 4872 Bethesda, MD 20892-4872 Telephone: (301) 594-3535 FAX: (301) 480-5450 Email: morsem@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 at the beginning of this document. The letter of intent should be sent to: Teresa Nesbitt, D.V.M., Ph.D. Chief, Review Branch, NIAMS, NIH, DHHS One Democracy Plaza 6701 Democracy Boulevard, Suite 800, MSC 4872 Bethesda, MD 20892-4872 Telephone: (301) 594-4953 FAX: (301) 480-4543 Email: nesbittt@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: Research Plan The research plan (a-d) is limited to 25 pages for R01 applications and 10 pages for R21 applications. Applications that exceed the page limit will be returned without review. An appendix may be included in the application; however, the appendix is not to be used to circumvent the page limit of the research plan. For the R21 application, preliminary data supporting feasibility of approach are not required; however, if included, the section may not exceed 1 page. In addition, a paragraph should be included in the Significance section of the application that specifies either 1) how the project presents a new direction for the work performed in the PI's laboratory or 2) the innovative nature of the research question or approach, and how it may advance the understanding of the role of innate immunity in rheumatic diseases. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/labels.pdf. SENDING AN APPLICATION TO THE NIH: 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 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix materials must be sent to: Teresa Nesbitt, D.V.M., Ph.D. Chief, Review Branch, NIAMS, NIH, DHHS One Democracy Plaza 6701 Democracy Boulevard, Suite 800, MSC 4872 Bethesda, MD 20892-4872 Telephone: (301) 594-4953 FAX: (301) 480-4543 Email: nesbittt@mail.nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 an RFA, it is to be prepared as a NEW application. That is, the application for the RFA 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAMS. Incomplete applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAMS in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the NIAMS Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, all R21 applications will also be reviewed with respect to the following: In the context of this RFA, the R21 exploratory/developmental grants are to be used to either: a) gather preliminary data to develop a research basis for a subsequent application through other mechanisms, i.e., R01, P01 or b) explore the feasibility of an innovative or conceptually creative research question or approach that may not be justifiable through existing research to compete as a standard research project grant (e.g., R01). Preliminary data supporting feasibility of approach are not required. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: November 19, 2003 Application Receipt Date: December 19, 2003 Peer Review Date: June 2004 Council Review: September 2004 Earliest Anticipated Start Date: September 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS 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). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific or ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 that is available at https://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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://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 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see 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. Applications that do not provide this information will be returned without review. PUBLIC 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 public 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 https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA 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. 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). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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 https://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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 RFA 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 or Health Systems Agency review. 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 and92. 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 https://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.
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