RFA-NS-00-002: NEUROBIOLOGY OF DIABETIC COMPLICATIONS

Department of Health
and Human Services (HHS)

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NEUROBIOLOGY OF DIABETIC COMPLICATIONS Release Date: January 13, 2000 RFA: NS-00-002 National Institute of Neurological Disorders and Stroke National Institute of Diabetes and Digestive and Kidney Diseases Juvenile Diabetes Foundation International Letter of Intent Receipt Date: March 24, 2000 Application Receipt Date: April 25, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA/PA. PURPOSE The National Institute of Neurological Diseases and Stroke (NINDS), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Juvenile Diabetes Foundation International (JDF) invite investigator-initiated research grant applications to study the neurobiology of diabetic complications. Research should be aimed at understanding the mechanisms by which diabetes results in painful, disabling peripheral neuropathy, autonomic neuropathy, impaired counterregulation and hypoglycemia unawareness, and other neurological complications. The intent of this RFA is to attract basic neuroscientists to the study of diabetic neuropathy and neurobiology relevant to diabetes, and enhance interdisciplinary approaches to research in this area. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Neurobiology of Diabetic Complications, is related to the priority area of diabetes and chronic diseases. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and the Exploratory/Development Research Grant (R21) award mechanisms. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators; 2) allow exploration of possible innovative new directions for established investigators; and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $100,000 direct costs per year and are limited to two years. These R21 grants will not be renewable; continuation of projects developed under this program will be through the regular research grant (R01) program. Except as otherwise stated in this announcement, awards will be administered under grants policy as stated in the NIH Grants Policy Statement. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is September 29, 2000. FUNDS AVAILABLE The NINDS and NIDDK intend to commit up to $3 million in FY 2000 to fund 15 to 20 new and/or competitive continuation grants in response to this RFA. The JDF intends to commit up to $1M in additional funds to co-fund research project grants that are both scientifically meritorious and fit within the mission and research emphasis areas of the JDF. (See http://www.jdfcure.org, for more information.). All awards will be issued by the NINDS and the NIDDK. An applicant may request a project period of up to 5 years for an R01. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NINDS, NIDDK, and JDF 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 applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Over 60 per cent of individuals with diabetes suffer from some form of neuropathy, and in many patients the symptoms are serious enough to interfere with daily activities. Small nerve fiber dysfunction typically occurs first in the lower extremities, where it is manifest by loss of thermal sensitivity and pin prick; pain and paresthesis are often present. Large fiber damage is characterized by reduced vibration perception, light touch and position sense, as well as weakness and depressed tendon reflexes. Diabetic peripheral neuropathy is often associated with peripheral vascular disease and impaired wound healing, resulting in more than 200,000 cases of foot ulcers and 80,000 amputations per year, with an annual medical cost of over $2 billion. In fact, diabetes is the leading cause of non-traumatic lower leg amputations in the United States. Symptoms of diabetic autonomic neuropathy can include heart rate abnormalities, blood pressure dysregulation, dizziness, digestive disturbances, and impotence. Autonomic neuropathy is thought to be an important cause of sudden cardiac death in patients with diabetes. Effective therapies for the prevention and treatment of diabetic neuropathy are not currently available. The Diabetes Control and Prevention Trial (DCCT) in patients with type 1 diabetes, and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetics have conclusively demonstrated that good glucose control significantly reduces the incidence of microvascular complications. With current treatment modalities, however, tight control remains an unattainable goal for many people with diabetes. In addition, metabolic abnormalities may impair neuronal function and lead to hypoglycemia unawareness, which limits the ability of a patient to undertake intensive insulin therapy. Thus, it is imperative that new approaches to prevent or ameliorate complications be developed. To design new, effective therapeutic modalities it is essential to understand the molecular basis for hyperglycemia-induced nerve damage. Mechanisms by which nerves may be injured in diabetes include microvascular compromise, demyelination, apoptosis, and altered metabolism. In the past, attention has been focused on hyperglycemia- induced changes in metabolism, including the induction of the polyol pathway, alterations in intracellular redox state, hyperosmolarity, abnormal PKC activation and glycation of proteins. Abnormalities in various neurotrophic factors have also been implicated in the development of diabetic neuropathy. Despite the progress that has been made in this area, the interrelationships between the various mechanisms of injury have not been systematically studied. Different mechanisms may play a dominant role at different stages of neuronal damage. The molecular basis for many of the relevant signaling pathways remains unknown. In addition, there have been significant advances in the realm of basic neurobiology that need to be studied in the context of diabetes. Relevant advances include research relating to apoptosis, neuronal regeneration, Schwann- axon cell interactions, neurotrophins, and the role of the vasculature in supporting neuronal function. Scope and Objectives The major focus of this RFA is to apply recent advances in the neurosciences to the study of the neurological complications of diabetes. Investigators with diverse scientific interests are invited to apply their expertise to basic and applied research to enhance our understanding of the pathogenesis of diabetic neuropathy, to develop appropriate models relevant to understanding and treating these complications, and to develop innovative strategies to prevent, limit, or reverse these complications. Applications may focus on peripheral neuropathy, autonomic neuropathy and/or hypoglycemia unawareness. It is highly desirable for basic neurobiologists to form collaborative efforts with diabetologists. Appropriate topics for investigation would include but are not limited to: o Studies of abnormalities in peripheral nervous system myelin synthesis, structure, and function in diabetic neuropathy o Studies of perturbations in end-organ/axonal trophic interactions in diabetic neuropathy o Development of improved experimental models for study of diabetic neuropathy in animals and in vitro o Studies of mechanisms involved in pain conditions associated with diabetic neuropathy and their relation to other neuropathic pain conditions o Studies of the mechanism of action and efficacy of potential therapeutic agents to relieve pain associated with diabetic neuropathy o Development of new non-invasive methods for early detection of neuropathy, which can function as surrogate endpoints for measuring the effectiveness of therapeutic interventions o Studies to identify determinants of peripheral nerve regeneration and aborted regeneration in diabetes. o Studies to define determinants of cell death of nerves or Schwann cells in diabetic neuropathy. o Studies to delineate the role of growth factors and/or cytokines in the pathogenesis of diabetic neuropathy and their utility in the prevention or treatment of neuropathy. o Studies to characterize the neuronal response to injury in diabetes. o Studies to develop clinically useful, surrogate markers for C-fiber damage. o Studies to evaluate diabetes-associated endothelial dysfunction in the vasa nervorum/endoneurium/perineurium. o Studies to understand the non-myelin trophic support role of Schwann cells. o Studies to define the role of peripheral nerves in regulating the biology of the epidermis and dermis. o Studies to determine the biochemical mechanisms of nerve damage, focusing on hyperglycemia-induced abnormalities. o Studies to determine the role of insulin in diabetic nerve damage. o Studies of the role of diabetic neuropathy in silent cardiac ischemia and/or increased peri-infarction mortality in patients with diabetes. o Studies to investigate the effect of abnormal glucose metabolism on hypothalamic and/or other CNS circuits that regulate autonomic function and detection of hypoglycemia. o Studies of the role of the nervous system in endocrine responses to hypoglycemia and how diabetes may alter the counterregulatory response. o Studies to determine the role of autonomic neuropathy in hypoglycemia unawareness. SPECIAL REQUIREMENTS Letter of Authorization Applicants should submit a brief letter to the NINDS indicating whether or not they wish their application to be considered for funding by the JDF. While applicants may request that their applications be considered only by the NIH and not by the JDF, it is necessary that the record indicate the applicant's consideration of this opportunity. For those applicants who wish to have the JDF consider their application, all materials relating to the application will be promptly forwarded to that organization and the summary statements for such applications will be shared with the JDF when available. This separate letter may be submitted with the Letter of Intent (see below). INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH 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 and 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 24, 2000, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions; and the number and title of the RFA in response to which the application may be submitted. 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 NINDS staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be mailed, faxed, or sent by e-mail to: Paul L. Nichols, Ph.D. NINDS Neuroscience Center, Room 2118 6001 Executive Blvd. Bethesda, MD 20892 Telephone: (301) 496-9964 FAX: (301) 402-2060 E-mail: pn13w@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov.The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The program announcement 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 available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application with the RFA number on 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 time of submission, two additional copies of the application must be sent to: Chief, Scientific Review Branch Division of Extramural Activities, NINDS Neuroscience Center, Room 3208 6001 Executive Blvd. Bethesda, MD 20892 Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. 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. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NINDS and NIDDK. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. 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 NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and receive a second level review by the Advisory Councils of NINDS and NIDDK. 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, reviewer will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. Schedule Letter of Intent Receipt Date: March 24, 2000 Application Receipt Date: April 25, 2000 Peer Review Date: July/August 2000 Council Review: September 2000 Earliest Anticipated Start Date: September 29, 2000 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Paul L. Nichols, Ph.D. NINDS Neuroscience Center, Room 2118 6001 Executive Blvd. Bethesda, MD 20892 Telephone: (301) 496-9964 FAX: (301) 402-2060 E-mail: pn13w@nih.gov Barbara Linder, M.D., Ph.D. DDEMD NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: linderb@extra.niddk.nih.gov Direct inquiries regarding fiscal matters to: Nancy Dixon Division of Extramural Activities NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8854 FAX: (301) 480-4237 E-mail: dixonn@extra.niddk.nih.gov Dawn Richardson Grants Management Branch NINDS Neuroscience Center, Room 3254 6001 Executive Blvd. Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0129 E-mail: da8h@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, 93. 853. Awards are under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99- 158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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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