PATHOGENESIS AND THERAPY OF COMPLICATIONS OF DIABETES NIH Guide, Volume 26, Number 38, November 21, 1997 RFA: DK-98-009 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Eye Institute National Heart, Lung, and Blood Institute National Institute on Aging National Institute of Dental Research National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 PURPOSE The Institutes listed above invite investigator-initiated research grant applications to study the mechanisms by which hyperglycemia results in the late complications of diabetes and to apply this information to the development of interventions to prevent, limit or reverse complications associated with type 1 diabetes. The Request for Applications (RFA) addresses pathogenic mechanisms common to the spectrum of complications of diabetes, as well as research directed specifically at diabetic neuropathy and retinopathy, and macrovascular and oral complications. A complementary RFA (DK-98-001) is focused on mechanisms, genetic determinants and interventions for diabetic nephropathy. A particular area of scientific opportunity, which is emphasized in this RFA, is the role of growth factors in the pathogenesis and/or therapy of complications of diabetes. The intent of this RFA is to intensify investigator-initiated research, to attract new investigators to the field and to enhance interdisciplinary approaches to research in these areas. 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, Pathogenesis and Therapy of Complications of Diabetes, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit 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 Support of this program will be through the National Institutes of Health (NIH) Research Project Grant (R01), Interactive Research Project Grant (IRPG), and Exploratory/Developmental Research Grant (R21) award mechanisms. Guidelines for preparing IRPG applications are available from the program official or from the internet at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html. The R21 awards are to demonstrate feasibility of a concept and to generate sufficient preliminary data to pursue it through other funding mechanisms. These grants are intended to (1) provide initial support for new investigators; (2) allow exploration of possible innovative new leads or 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. Applicants from institutions that 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. If so, 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. Applicants anticipating submitting IRPG applications or applicants requesting more than $500,000 direct costs in any year should consult with the NIDDK Program Official listed under INQUIRIES at an early opportunity. Applicants must receive permission from the NIDDK prior to the submission of an application requesting more than $500,000 in direct costs per year for any year of the proposed study. NIDDK staff will coordinate consideration and acceptance of such large applications by the staff of the appropriate Institute. The total requested project period for an application submitted in response to this RFA may not exceed three years. Budget escalations in future years are limited to three percent of recurring costs. The anticipated award date is September 30, 1998. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under Public Health Service (PHS) grants policy as stated in the PHS Grants Policy Statement. FUNDS AVAILABLE For FY 1998, $6 million will be committed to fund applications submitted in response to this RFA. It is anticipated that approximately 25 awards will be made. However, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. The award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Prevention and treatment of chronic complications is a central therapeutic problem in type 1 diabetes mellitus. In the United States, diabetes is the leading cause of new blindness in people age 20-74, and accounts for 35% of all new cases of end-stage renal disease. Over 60% of people with diabetes are affected by neuropathy, and accelerated lower extremity arterial disease in conjunction with neuropathy makes diabetes account for 50% of all nontraumatic amputations in the United States. In addition, macrovascular complications are a major cause of morbidity and mortality in diabetes, particularly in individuals with nephropathy. Diabetes also confers a markedly increased risk of developing oral complications. The Diabetes Control and Complications Trial (DCCT) demonstrated that exposure to glycemia as measured by mean glycated hemoglobin (HbA1c) is the dominant predictor of retinopathy and nephropathy, and that intensive therapy reduced appearance and progression of these complications by 45% to 78%. Intensive therapy did not significantly reduce macrovascular complications, although there was a non-significant trend towards reduced risk. However, many patients are not able to achieve near euglycemia, providing an imperative to develop new approaches to prevent or ameliorate complications. Several mechanisms by which hyperglycemia may damage cells and tissues have been identified. These include increased polyol pathway activity and associated changes in intracellular redox state, increased diacylglycerol synthesis with consequent activation of specific protein kinase C (PKC) isoforms, increased nonenzymatic glycation of both intracellular and extracellular proteins, and increased formation of reactive oxygen species. Tissue injury then results from acute changes in protein function and chronic changes in gene expression. It is likely that the pathologic effectors induced in different tissues by these mechanisms are specific for each particular complication (e.g., VEGF in diabetic retinopathy and TGF-beta in diabetic nephropathy). Evidence that abnormal PKC activation, abnormal protein glycation and increased flux through the polyol pathway play prominent roles in the pathogenesis of complications is particularly strong in animal models, since a specific PKC isoform inhibitor prevents diabetes-induced changes in retinal blood flow and glomerular filtration rate, while an inhibitor of advanced glycation product formation prevents retinal acellular capillary formation and increased mesangial volume. Both agents prevent diabetes-induced albuminuria. Similarly, treatment with an aldose reductase inhibitor prevents nerve conduction velocity slowing. Antioxidants such as vitamin E and lipoic acid also partially prevent several early vascular and neurological abnormalities in diabetic animals. Although much progress has been made, the possible interrelationships between these various hyperglycemia- accelerated pathways have not been systematically studied. Different mechanisms may play a dominant role at different stages or in different cell types or target tissues. Also, development of interventions for modifying known pathways is limited, and many molecular elements of relevant signaling pathways are unknown. Scope and Objectives Investigators with diverse scientific interests are invited to apply their expertise to basic and applied research to enhance our understanding of the pathogenesis of complications of diabetes, to develop appropriate models relevant to understanding and treating these complications, to develop innovative strategies to prevent, limit or reverse these complications, and to test new approaches to therapy. Investigators may wish to make use of samples (plasma, serum, urine) from the 1441 subjects with type 1 diabetes enrolled in the DCCT and followed for a mean of 6.5 years for the appearance and progression of retinopathy and other complications. For further information on this resource, see the Notice of Availability of Biologic Samples from Diabetic Study Population which appeared in the January 10, 1997 NIH Guide. Examples that illustrate areas to be considered within the intent of this solicitation are presented below. The following examples are intended only to provide a broad direction and should be considered illustrative, and not restrictive: o Determine the sequence of events in the pathogenesis of hyperglycemia-induced injury so that potential sites for intervention in this chain of events can be identified o Examine the molecular and cellular mechanisms by which hyperglycemia mediates its adverse effects and the interrelationships among these mechanisms, including: increased polyol pathway flux, alterations of intracellular redox state, oxidative stress, glycation of structural and functional proteins, altered expression of growth factors, enhanced activity of PKC, impaired synthesis of nitric oxide and vasoactive prostacyclins, and altered metabolism of fatty acids o Define the mechanisms by which the biochemical changes resulting from hyperglycemia mediate functional changes, such as altered blood flow, and anatomical changes o Define the utility (alone or in combination) and mechanisms of action in preventing or attenuating cell and tissue damage and neural dysfunction of aminoguanidine, antioxidants, transition metal chelators, aldose reductase inhibitors, PKC beta isoform inhibitors, nitrovasodilators, essential fatty acids, prostacyclin analogs, human C-peptide, and other potential therapeutic agents o Develop novel agents which may be effective in preventing or attenuating complications such as modulators of growth factor expression or activity, or inhibitors targeting discrete steps of the glycation pathway o Develop new transgenic and gene deletion animal models to elucidate the elements involved in hyperglycemia-induced activation/inhibition of gene expression o Identify genetic modulators of the susceptibility of tissues to hyperglycemia- induced injury o Develop surrogate endpoints (intermediate phenotypes) to identify subjects for genetic analysis o Develop methods to measure microvascular function, examine capillary permeability, identify the initial vascular cell responses to hyperglycemia, and detect accelerated endothelial cell death before the development of morphological abnormalities o Define the mechanisms by which PKC activation modulates processes involved in complications, including vascular cell growth, permeability and gene expression o Determine how advanced glycation end product (AGE) accumulation could lead to cellular injury and widespread tissue dysfunction, by delineating AGE's effects on vascular matrix, permeability and/or relaxation, growth factor expression, inflammatory responses, and cellular activation and function o Identify the mechanisms and biochemical and genetic components involved in basement membrane thickening in diabetes o Elucidate the initiating mechanism for injury in experimental diabetic retinopathy o Identify the chain of events leading to increased VEGF production in vivo in proliferative retinopathy o Develop and study models useful for investigating the effects of VEGF on vascular leakage and neovascularization, and for identifying inhibitors of ocular neovascularization o Develop VEGF inhibitors or other methods of reducing the bioavailability of VEGF o Study the role of growth hormone and other growth factors in the pathogenesis of diabetic retinopathy o Investigate the fundamental molecular and cellular mechanisms involved in hyperglycemia-induced nerve dysfunction o Delineate the role of NGF and other neurotrophic factors in pathogenesis of diabetic neuropathy and their utility in prevention and amelioration of diabetic neuropathy o Develop methods for targeted delivery of neurotropins o Define the role of microangiopathy in the pathogenesis of diabetic neuropathy o Define the mechanisms by which metabolic changes of diabetes exert a negative impact on nerve blood supply o Identify mechanisms by which hyperglycemia increases mammalian nerve oxidative stress, including hyperglycemic autoxidation-glycation and endoneurial lipid peroxidation o Develop improved methods to characterize and quantitate diabetic neuropathy in humans and animal models that can serve as standardized surrogate endpoints or outcome measures in clinical and animal studies o Determine ways in which hyperglycemia can produce vascular injury that may initiate or accelerate macrovascular complications of diabetes o Develop therapeutic strategies, independent of glucose, hypertension or lipid control, to block the effects of sustained hyperglycemia on progression of atherosclerosis o Study the effect of growth factors on the progression of macrovascular complications of diabetes looking for common and dissimilar effects from those involved in the pathogenesis of diabetic microvascular complications o Determine the mechanisms by which hyperglycemia and growth factors cause oral complications of diabetes, including effects on oral connective, vascular and neural tissues o Study effects of age-related physiologic changes on the rates of progression of complications of type 1 diabetes, and their underlying mechanisms. 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 sub-populations 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 have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit by February 19, 1998, 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 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 NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F - MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) 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 301/435-0714, email: ASKNIH@od.nih.gov. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. 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. As indicated under MECHANISM OF SUPPORT, if a collaboration (IRPG) of individual investigators is planned, it is necessary to identify one of the investigators as the group coordinator and to cite this individual in all applications on page 2 of the form PHS 398 (rev. 5/95). Applicants who have entered into a collaboration may submit the applications individually with a cover letter noting their involvement and listing the other members of the collaboration. Submit a signed, typewritten original of the application, including the Checklist, plus 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, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F - MSC 6600 BETHESDA, MD 20892-6600 Applications must be received by March 19, 1998. If an application is received after that date, it will be returned to the applicant without review. 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 Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with 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 will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council of the assigned Institute(s). Review Criteria 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 methods? 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? o Appropriateness of the proposed budget and duration in relation to the proposed research. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will be evaluated. The initial review group will also examine the provisions for the protection of human and animal 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 United States resources. o For those applications that propose collaborative efforts between several applicants, additional factors to be considered during the review would include the efficacy of the collaboration, the commitment of the participants to the collaboration, the design and responsibilities of the coordinating center and the cost effectiveness of the collaborative effort. R21 applications will have the additional review criteria: o Potential for novel and innovative approaches that clearly require additional preliminary data for their value to be established. IRPG applications will have these additional review criteria: o Each component R01 of the IRPG will be reviewed as above for its independent scientific merit. o The reviewers will assess the intended IRPG interactions, including the effectiveness and feasibility of the proposed IRPG group interactions, whether or not they enhance the prospects for reaching the stated objectives of the group, and the extent of synergy among the various projects. AWARD CRITERIA The anticipated date of award is September 30, 1998. The factors that will be used to make award decisions include: o scientific and technical merit as determined by peer review, o availability of funds, and 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: Judith Fradkin, M.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 5AN-12E - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8814 FAX: (301) 480-3503 Email: jf58s@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.nih.gov Peter J. Savage, M.D. Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 8104 Bethesda, MD 20892-7938 Telephone: (301) 435-0421 FAX: (301) 480-5298 Email: ps47h@nih.gov Pamela E. Starke-Reed, Ph.D. Office of Nutrition National Institute on Aging Gateway Building, Room 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: PS39P@NIH.GOV Dennis Mangan, Ph.D. Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN-32F Bethesda, MD 20892-6402 Telephone: (301) 594-2421 FAX: (301) 480-8318 Email: ManganD@de45.nidr.nih.gov Paul L. Nichols, Ph.D. Division of Convulsive, Infectious, and Immune Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 504 Bethesda, MD 20892 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: pn13w@nih.gov Direct inquiries regarding fiscal and administrative matters to: Nancy C. Dixon Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8854 FAX: (301) 480-4237 Email: dixonn@extra.niddk.nih.gov 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 William Darby Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7128 Bethesda, MD 20892-7128 Telephone: (301) 435-0177 FAX: (301) 480-3310 Email: William_Darby@nih.gov Robert Pike Grants and Contracts Management Office National Institute on Aging Gateway Building, Room 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 Email: Pikeb@exmur.nia.nih.gov Martin R. Rubinstein Division of Extramural Research National Institute of Dental 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 Federal Building, Room 1004 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: da8h@nih.gov SCHEDULE Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 Initial Review: June/July 1998 Second Level Review: September 1998 Anticipated Date of Award: September 30, 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 ("Diabetes, Endocrinology and Metabolic Diseases), 93.867 ("Vision Research"), 93.387 ("Heart and Vascular Disease"), 93.866 ("Aging Research"), 93.121 ("Oral Diseases and Disorders Research Awards"), 93.853 ("Clinical Research Related Neurological Disorders"), 93.854 ("Biological Basis Research in the Neurosciences"). 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. 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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