DIABETIC NEPHROPATHY: MECHANISMS, GENETIC DETERMINANTS, INTERVENTIONS NIH GUIDE, Volume 26, Number 32, September 26, 1997 (see NOT-DK-05-001) RFA: DK-98-001 P.T. National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: December 9, 1997 Application Receipt Date: January 9, 1998 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through its Division of Kidney, Urologic and Hematologic Diseases (DKUHD) invites experienced and new investigators to submit research grant applications to pursue basic and applied investigations in order to better understand the pathophysiology of diabetic nephropathy, the genetic determinants of susceptibility, and cellular and molecular factors; mechanisms of glomerulosclerosis, interstitial fibrosis and renal scarring; development of experimental model systems that mimic human disease to better the understanding of the pathogenetic mechanisms and to test agents to prevent, stabilize or reverse complications; identification of sensitive and relevant markers of disease initiation and progression; identification of innovative therapeutic interventions and gene targeted strategies to prevent, limit, or reverse renal lesions due to this disorder. The intent of the Request for Applications (RFA) is to intensify investigator-initiated research, to attract new investigators to the field, and to increase interdisciplinary research to enhance the scope and effectiveness of research in this area. The ultimate aim is to encourage and facilitate diabetes nephropathy-related studies utilizing new tools and taking advantage of opportunities in other fields to increase the pace with which knowledge is accrued. 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, "Kidney Disease of Diabetes: Mechanisms, Genetics, Interventions", is related to the priority area of chronic disabling diseases. 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 Research grant applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. 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 Grants (R01), Interactive Research Project Grants (IRPG), FIRST Award (R29), and Exploratory Research Grants (R21) award mechanisms. FIRST Award applications must adhere to the R29 administrative guidelines (rev. June 1995) for eligibility, budget, and period of award. Applications from Institutions with 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. 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. 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. For R01s, the total requested project period for applications submitted in response to this RFA may not exceed 5 years. A maximum of three-years can be requested for foreign awards. In general, the maximum budget request should be limited to $160,000 in direct costs for the initial budget period. Requests for support that exceeds that amount will require a thorough justification, and in no case will a request exceeding $250,000 direct cost for the initial budget period be allowed under this solicitation. Applicants anticipating submitting Interactive Research Program Grant (IRPG) Applications should consult with the Program Official listed under "INQUIRIES" at an early opportunity. Applications for Exploratory Research Project Grant Applications (R21) awards may apply for no more than $50,000 direct costs per year, for a maximum of two years. The anticipated award date is July 1, 1998. FUNDS AVAILABLE A total of $ 2.5 million in total cost will be committed by the NIDDK to fund applications of high scientific merit submitted in response to this RFA. It is anticipated that 10-12 awards will be made. Although this program is provided for in the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background: Diabetic nephropathy has emerged as the largest single cause of end stage renal failure in the United States. It accounts for nearly 40% of the 60,000 to 70,000 new patients who need dialysis each year. Diabetic patients do poorly on dialysis, with high rates of infection, access failure, and cardiovascular complications. Of all long-term complications of diabetes, nephropathy imposes the highest costs, both in dollars and in terms of human suffering. Concerning the genetic implications, diabetic nephropathy does not necessarily develop in all diabetic patients, the incidence of end stage renal failure being about 30% in patients with insulin-dependent diabetes mellitus (IDDM) and approximately 4-20% in patients with non-insulin-dependent diabetes mellitus (NIDDM). There is now strong evidence that genetic factors influence susceptibility to this condition. A variety of new strategies are available to characterize the genetic determinants for the development and progression of diabetic nephropathy. Included are the identification of new candidate susceptibility genes using methods of molecular genetics such as differential display or others; examination of the role of putative candidate genes in the onset and progression of diabetic nephropathy using family studies and transmission disequilibrium testing (TDT); identification of chromosomal regions containing genes responsible for susceptibility through family (linkage) studies and, potentially, once such regions are identified, positional cloning of the putative genes, etc. Concerning the pathophysiology of the disease, new insights also suggest new productive avenues for research. In virtually all patients, diabetes mellitus initially leads to diffuse renal hypertrophy and basement membrane thickening. Much early investigation focused on the pathogenesis of these lesions. Progression of these early markers is highly variable, however. In many patients, the early lesions are not followed by the development of glomerular scarring. Much of the available evidence suggests that scarring of the glomerulus arises from interactions between the microvasculature and the surrounding cell types. Specific topics needing further study include the mechanism by which hemodynamic factors potentiate injury, the role of cytokines and growth factors in regulation of scarring, particular stress responses, role of the renin-angiotensin system and aldosterone, the role of epithelial cells in the genesis of glomerular injury, the elucidation and characterization of the biochemical composition of the expanded matrix in diabetic nephropathy, the role of the polyol pathway activity, non-enzymatic glycation, advanced glycosylation end-products (AGES), redox changes, formation of reactive oxygen species, and the possible interrelationship of the mechanisms listed above in different cell types and tissues and in the different stages of the natural history and progression of diabetic nephropathy. Further work is needed in the development of animal models which mimic human disease, as well as models using genetically modified mice in which the effect of over- or underexpression of candidate susceptibility genes is examined. This may permit direct examination of genetic factors which determine the development and progression of the renal injury. Concerning the need to identify markers which will permit early identification of patients at risk of developing renal disease, the best currently available clinical tool for early identification of diabetic nephropathy remains the quantitative assessment of urinary albumin excretion. Prospective epidemiological information is needed to assess the predictive value of this measure, together with other clinical parameters in various population groups. Scientific Objectives: (1) To identify genes whose altered function predispose to diabetic nephropathy and to understand the mechanisms by which these genetic alterations enhance susceptibility. (2) To understand the underlying mechanisms leading to progressive renal scarring in diabetic nephropathy. (3) To identify markers which will permit early identification of patients at increased risk for diabetic nephropathy. Research Scope: It is the intent of this solicitation to invite applications from investigators with diverse scientific interests, who wish to apply their expertise to basic and applied research to enhance the understanding of the pathophysiology and pathogenesis of diabetic nephropathy; the genetic determinants and genetic factors influencing susceptibility, and cellular and molecular mechanisms and interplay that lead to the development of glomerulosclerosis and tubulointerstitial fibrosis and scarring; the development of experimental model systems in which the expression of susceptibility genes is examined; the identification of markers to ascertain when the process starts and when disease progresses; the identification of therapeutic opportunities and potentially gene targeted strategies to prevent or control scarring and progressive renal insufficiency in diabetic nephropathy. Examples which illustrate areas to be considered within the intent of this solicitation are presented in the following paragraphs. These examples are meant only to provide a broad direction and should be considered illustrative, and not restrictive. Examples, include the following: 1. Pathogenetic Mechanisms o Role, mechanisms of action and interplay of growth factors and other cytokines in regulating glomerular and interstitial sclerosis and scarring; studies addressing molecular elements of relevant signaling pathways. o Definition of the sequence of events in the pathophysiology of diabetic nephropathy, at the molecular and cellular levels and characterization of the molecular elements of relevance in signaling pathways. o Pathobiology of glomerular epithelial cells as well as role of glomerular endothelial cells, in-vivo, as players in the injury process. o Interaction between the microvasculature and the surrounding cell types in glomerulosclerosis, tubulo-interstitial fibrosis and scarring, in diabetic nephropathy. o Effect of insulin therapy and counter regulatory hormones on glomerular and interstitial sclerosis and extracellular matrix synthesis, composition, and response. o Interrelationship of biochemical mechanisms leading to matrix expansion and the development of scarring in diabetic nephropathy, including, but not limited to the polyol pathway activity, advanced glycosylation end-products (AGES), redox changes and formation of reactive oxygen species in different cell types and tissues in the different stages of diabetic nephropathy. o Role of hemodynamic and vasoactive factors, renin-angiotensin system, aldosterone and inhibitors, with an effect either over vascular tone or as trophic factors affecting mRNA expression for extracellular matrix components and vascular smooth muscle proliferation. o Identification and characterization of susceptibility factors for renal sclerosis and of putative risk factors for the onset of microalbuminuria and progression of diabetic nephropathy. 2. Genetic Considerations o Identification and characterization of genetic determinants for the development and progression of human diabetic nephropathy. o Identification of new candidate susceptibility genes using methods of molecular genetics such as differential display or others. o Role of putative candidate genes in the onset and progression of diabetic nephropathy using family studies and transmission disequilibrium testing. o Identification of chromosomal regions containing genes responsible for susceptibility through family (linkage) studies and potentially, once such regions are identified, positional cloning of the putative genes, etc. 3. Therapeutic Strategies o Identification of early quantitative markers of disease and sensitive markers of progression, and identification of adequate outcome measures to judge the effect of clinical interventions in early stages of the disease. o Identification of novel interventions and new targets for prevention and treatment of renal fibrosis in diabetic nephropathy. Mesangial deposition seems to be reversible and glycosylated proteins remain biodegradable, offering hopes for future therapy. o Gene therapy and sequence-specific methods for modifying gene expression in the kidney; development of techniques suitable for modifying expression of gene products that accelerate progression of diabetic nephropathy. o Trial of agents that prevent, stabilize or reverse complications in animal models of diabetic nephropathy. 4. Markers o Identification of markers for early recognition of diabetic renal disease in patients at increased risk for diabetic nephropathy. o Identification of sensitive and specific surrogate end-points for the development of diabetic nephropathy, other than GFR and albumin excretion which, are either non-specific or not sensitive enough. o Formulation of prospective epidemiologic strategies to assess the predictive value of quantitative markers, together with other relevant clinical parameters in various population groups. 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 20, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy 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 December 9, 1997, 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 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. Applications kits 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: ASKNIH@od.nih.gov. Applicants for FIRST (R29) awards must submit at least three letters of reference, with the application. FIRST (R29) award applications received without the three reference letters will be returned to the applicant. 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. Submit a signed, typewritten original of the application, including the Checklist, plus three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS 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 January 9, 1998. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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 will be reviewed for completeness by DRG and responsiveness by the NIDDK. 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 NIDDK 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 Diabetes and Digestive and Kidney Diseases 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. 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?" 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 also 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. For applications awarded to foreign institutions: 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 Applications recommended for funding will considered on the basis of the following: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Gladys H. Hirschman, M.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS13 - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: gladys_hirschman@nih.gov Inquiries regarding fiscal and administrative matters may be directed to: Aretina D. Perry-Jones Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Building 45 Room 6AN-38 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8862 FAX: (301) 480-3504 SCHEDULE Application receipt dates, initial review, and award cycles will be: Letter of Intent Receipt Date: December 9, 1997 Application Receipt Date: January 9, 1998 Initial Review Date: March-April 1998 Advisory Council Review: May 1998 Anticipated Date of Award: July 1, 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849. 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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