THE ROLE OF GROWTH FACTORS IN THE DEVELOPMENT OF DIABETES COMPLICATIONS Release Date: September 2, 1999 PA NUMBER: PA-99-159 National Institute of Diabetes and Digestive and Kidney Diseases National Eye Institute National Institute for Dental and Craniofacial Research National Institute of Neurological Disorders and Stroke National Heart, Lung, and Blood Institute THIS PA USES THE "MODULAR GRANT" AND JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Eye Institute (NEI), National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Neurological Disorders and Stroke (NINDS), and National Heart, Lung, and Blood Institute invite investigator- initiated research grant applications to study the role of growth factors in the etiology and pathogenesis of the micro- and macrovascular complications of diabetes. While several growth factors are already being tested in clinical trials for the treatment and/or prevention of diabetic microvascular disease, a systemic examination of the pathophysiologic role of growth factors in diabetic complications is lacking. This PA, with a $2 million NIDDK annual set-aside, is intended to stimulate the application of new molecular technologies to this area. An understanding of the tissue and cell specific expression of growth factors in the eye, kidney, mouth, nerves and vessels, and of the molecular action of these growth factors in the pathophysiology of complications will lead to improved and more specific therapies. 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 PA, The Role of Growth Factors in the Development of Diabetes Complications, is related to the priority area of diabetes and chronic disabling conditions. 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 PA will use the National Institutes of Health (NIH) research project grant (R01) and 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). This PA will use the modular grants application and award process. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 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. Refer to instructions under APPLICATION PROCEDURES, below. Complete and detailed instructions and information on Modular Grants can be found at https://grants.nih.gov/grants/funding/modular/modular.htm Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. FUNDS AVAILABLE $2 million per year will be set aside by the NIDDK to fund applications relevant to this PA. NEI, NIDCR, NINDS, and NHLBI are interested in applications relevant to this topic but have not set aside specific funds. Funding is dependent on the receipt of a sufficient number of applications of high scientific merit and on the availability of funds for this purpose. This PA will remain active for three years, through the receipt date of October 1, 2002. RESEARCH OBJECTIVES Background The micro- and macrovascular complications of diabetes are a major public health concern. Diabetic retinopathy is the predominant cause of blindness in adults, and diabetic nephropathy is a leading cause of end-stage renal disease. Diabetes is the most common reason for non-traumatic lower extremity amputations and over 50% of patients with diabetes experience some degree of neuropathy. Diabetes results in a greater incidence and severity of periodontal diseases and other oral mucosal infections, and these infections can make it harder to control blood glucose levels. Finally, accelerated cardiovascular disease remains the major cause of mortality in patients with diabetes. The pathologic findings seen in diabetic microvascular complications, as well as in atherosclerosis, implicate growth factors in their development. For example, endothelial proliferation in the eye results in abnormal neovascularization of the retina. In the kidney, accumulation of mesangial matrix is the hallmark of diabetic nephropathy. Atherosclerotic lesions are also known to involve the accumulation of extracellular matrix, as well as proliferation of smooth muscle cells. Studies strongly suggest a role for vascular endothelial growth factor (VEGF) in the pathogenesis of diabetic proliferative retinopathy. VEGF levels are increased in the vitreous of animals and humans with diabetic retinopathy, and agents which antagonize VEGF will suppress neovascularization of the retina. Although the available data indicate that VEGF is likely to play a critical role in the pathogenesis of diabetic retinopathy, its exact mechanism at the molecular level is not understood. Studies are needed to understand not only the cascade of events triggered by VEGF, but how hyperglycemia leads to VEGF upregulation. In the kidney, transforming growth factor (TGF)-beta appears to contribute to the basement membrane thickening characteristic of diabetic nephropathy. TGF- beta levels are elevated in the early stages of nephropathy and inhibition of TGF-beta appears to prevent glucose-induced stimulation of extracellular matrix synthesis in vitro. Levels of other growth factors, including insulin- like growth factor 1 (IGF-1), fibroblast growth factor (FGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF), are also altered; however, the role of these other growth factors in the pathogenesis of diabetic retinopathy and nephropathy is less well characterized than for VEGF and TGF-beta. Altered cytokine (e.g., tumor necrosis factor) expression may also contribute to endothelial dysfunction in diabetes. Many growth factors and cytokines, including EGF, TGF-beta, TNF-alpha and IGF- 1, require interaction with matrix-associated proteases for release as soluble proteins that can interact with and activate receptors. Perturbations in this critical processing step have been implicated in a variety of neurodegenerative and inflammatory disorders. Angiotension converting enzyme (ACE) is also processed to its active form by matrix proteases. ACE inhibitors are used extensively in patients with diabetes to reduce proteinuria and prevent the progression of diabetic nephropathy, although their exact renal-protective mechanism of action remains poorly understood. High levels of gingival crevicular prostaglandins (PGE2) and cytokines (TNF- alpha, IL-1 beta) are found in type 1 diabetic patients with periodontitis. Excess monocytic pro- and anti-inflammatory factors may lead to abnormal wound healing, tissue destruction and chronic infection in the oral mucosal tissues. In addition, high levels of extracellular glucose induce the over-expression of fibronectin receptors on periodontal ligament cells, suppressing their ability to migrate in a normal fashion to PDGF. Such abnormal movement of the ligament cells could exacerbate the severity and duration of the periodontal lesion. Growth factor deficiency, rather than upregulation, is thought to play a role in the pathogenesis of diabetic neuropathy. Studies have demonstrated reduced levels of nerve growth factor (NGF) and IGF-1 in animals and humans with diabetic neuropathy; however, no direct connection has been made between reduced levels of neurotrophic factors and the development of diabetic neuropathy. In addition, there are multiple members of the nerve growth factor family, each of which is specifically trophic for a different neuronal population. Studies are needed to examine not only tissue-specific but cell- specific expression of growth factors. Despite much suggestive evidence implicating growth factors in the development of the complications of diabetes, much remains to be determined about their role in the pathophysiology of these disorders. Little is known about how multiple growth factors might interact with each other in a specific tissue; nor is it known how growth factors interface with other abnormalities that have been implicated in the etiology of complications, including altered metabolism of polyols, accumulation of advanced glycation end products, activation of protein kinase C or increased reactive oxygen species. Finally, study of the pathophysiology of diabetic complications in humans is often limited by the inability to sample tissues and by the long time that it takes for complications to develop. There is clearly a need for the development of good animal models of diabetic complications, as well as of surrogate markers that would be useful for monitoring the development and progression of complications. The use of such markers would also facilitate the study of potential pharmacologic agents that could be developed, based on a better understanding of the etiology and pathogenesis of these complications. Objectives and Scope New technologies, including the use of genetic knockouts, transgenic animals and chip array technology, provide powerful tools for studying the expression of growth factors during the development of the micro- and macrovascular complications of diabetes, and for determining the molecular basis for their actions. Appropriate topics for investigation would include, but are not limited to: o Studies to evaluate the tissue and/or cell specific expression of various growth factors during the development of complications, including a temporal analysis. o Studies to determine if activation or release of growth factors by matrix proteases is altered in diabetes. o Studies to determine what genes are up- or down-regulated by altered growth factor expression. o Studies to determine if growth factor signaling pathways are altered in diabetic complications. o Studies to determine how hyperglycemia alters growth factor expression or action. o Studies to determine how other metabolic abnormalities associated with complications interact with alterations in growth factor expression and/or action. o Studies to test the role of growth factors in the pathogenesis of diabetic complications using animal models (including the use of knockout or transgenic animals). 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 new 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: https://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: https://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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or 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. Applicants planning to submit an investigator-initiated new (type 1) competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact NIH program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the staff that the NIH will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at https://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 https://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: https://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. Submit the signed, original, single-sided application, including the Checklist, along with five signed photocopies and five collated sets of appendix materials 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) The Center for Scientific Review (CSR) will not accept any application in response to this PA 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 already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established NIH referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second-level review by the appropriate national advisory council or board. 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. o 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? o 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? o 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? o 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)? o 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. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. 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. AWARD CRITERIA The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review; o Availability of funds; o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara Linder, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 5AN18A, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-0021 FAX: (301) 480-3503 Email: linderb@extra.niddk.nih.gov Peter A. Dudley, Ph.D. Vision Research Program National Eye Institute Executive Plaza South, Room 350 Bethesda, MD 20892 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: pad@nei.hin.gov Dennis Mangan, Ph.D. Division of Extramural Research National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-32E, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-2421 FAX: (301) 480-8318 Email: Dennis.Mangan@nih.gov Paul L. Nichols, Ph.D. National Institute of Neurological Disorders and Stroke Neurosciences Center, Room 2118 Bethesda, MD 20892 Telephone: (301) 496-9964 FAX: (301) 401-2060 Email: pn13w@nih.gov Dr. Thomas Blaszkowski Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute Rockledge 2, Room 8106, MSC 7938 Bethesda, MD 20892-7938 Telephone: (301) 435-0417 FAX: (301) 480-1864 Email: tb33i@nih.gov Direct inquiries regarding fiscal and administrative matters to: Florence Danshes Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8861 Margie Baritz Division of Extramural Activities National Eye Institute Executive Plaza South, Room 350 Bethesda, MD 20892-6600 Telephone: (301) 496-5884 FAX: (301) 496-9997 Email: Mbaritz@nei.nih.gov Martin Rubinstein Division of Extramural Research National Institute of Dental and Craniofacial Research Building 45, Room 4AN-44A Bethesda, MD 20892-6402 Telephone: (301) 594-4800 Email: Martin.Rubinstein@nih.gov Dawn Richardson Grants Management Branch National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 3254 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0129 Email: da8h@nih.gov Ms. Jane R. Davis Grants Management Office National Heart, Lung, and Blood Institute 6702 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0165 FAX: (301) 480-3310 Email: jane_davis@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, 93.867, 93.121, 93.853, 93.837, and 93.854. Awards are made 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 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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