RFA-DK-99-013: PILOT STUDIES FOR NEW THERAPIES FOR TYPE 1 DIABETES AND ITS COMPLICATIONS

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PILOT STUDIES FOR NEW THERAPIES FOR TYPE 1 DIABETES AND ITS COMPLICATIONS Release Date: January 8, 1999 RFA: DK-99-013 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Center for Research Resources National Eye Institute National Heart, Lung and Blood Institute National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development National Institute for Dental and Craniofacial Research Letter of Intent Receipt Date: March 1, 1999 Application Receipt Date: March 30, 1999 PURPOSE This Request for Applications (RFA) encourages applications for pilot and feasibility studies proposing innovative strategies for prevention or treatment of type 1 diabetes or its complications. Applications may also propose to explore truly novel hypothesis about the pathogenesis of type 1 diabetes or its complications but only if the hypothesis will identify new targets for intervention and generate new therapeutic strategies. Particularly relevant to this solicitation are proposals for development of surrogate markers, which can be used as outcome measures for clinical research in diabetes. This solicitation is especially designed to encourage submission of applications for high risk/high impact research and to encourage talented new investigators and established investigators not currently working in the area of diabetes to apply their expertise to developing new approaches to prevention and treatment of type 1 diabetes and its complications. 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, Pilot Studies to Develop New Therapies for Diabetes and Its Complications, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html 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. The pilot and feasibility studies are intended to: (1) provide initial support for new investigators, (2) allow exploration of innovative new leads or new directions for established investigators in diabetes, and (3) stimulate investigators from other areas to lend their expertise to research in this area. Pilot and feasibility grants are not intended to support or supplement ongoing funded research of an established investigator. This program enables investigators to explore the feasibility of a novel concept related to development of new therapies for type 1 diabetes and its complications and generate sufficient data to pursue it through other funding mechanisms. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) exploratory/ developmental grant (R21) award mechanism. These awards are to demonstrate feasibility and obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. FUNDS AVAILABLE Funding of 25 to 30 applications submitted in response to this solicitation is anticipated contingent on receipt of a sufficient number of high quality applications. $4 million (total costs) are available for this purpose in FY 1999. Applicants may request up to two years of support and up to $100,000 per annum in direct costs. The award is non-renewable. Continuation of projects developed under this program will be through the regular research project grant program. RESEARCH OBJECTIVES Background Type 1 diabetes results from immune destruction of the beta cells of the pancreas leading to loss of insulin secretion and resultant hyperglycemia. Therapy with insulin prevents ketoacidosis but does not presently prevent the devastating complications of diabetes. This RFA is to support pilot projects that focus on the development of new therapeutic approaches for the prevention or treatment this disease. Modulation of the specific immune response(s) leading to diabetes is the most promising area of research for the prevention of disease. There is evidence that arrest of the destructive immune response even after hyperglycemia has occurred may allow recovery of islet function. Identification of the mechanisms by which genetic loci place individuals at risk for the development of an autoimmune response and the mechanism by which some genetic loci protect individuals from development of disease may lead to new strategies to prevent and treat diabetes. It is likely that environmental and/or infectious agents yet to be identified also play an important role in the pathogenesis of the disease. The mechanisms by which these exogenous factors trigger or perpetuate the self-reactive immune response offer additional avenues for interventions. Recently identified regulatory pathways in the immune system, including co-stimulatory molecules, epitope spreading, cytokines, chemokines, and immunomodulatory networks are another site for modification of the autoimmune response leading to type 1 diabetes. This solicitation is intended to capitalize on our current understanding for the development of new therapies for type 1 diabetes. Establishing new methods to achieve and maintain euglycemia will have enormous impact on the health and quality of life of individuals with diabetes. The Diabetes Control and Complications Trial has established that metabolic control is highly effective in preventing or delaying the onset of diabetic complications. Unfortunately, present methods for achieving euglycemia are difficult to implement and expensive. Innovative approaches for achieving better metabolic control in type 1 diabetes are urgently needed. Closed-loop delivery systems combining mechanical insulin delivery devices and glucose sensing technology hold great promise for improving metabolic control and quality of life for individuals with diabetes. Cellular approaches to insulin replacement are under development, including islet transplantation and use of new techniques in cell biology and gene therapy to provide novel sources of insulin-secreting cells. Islet cell transplantation has been hampered by limited availability of viable islets, toxicity of immunosuppressive drugs, and ongoing autoimmune destruction of transplanted islets. New methods of immune modulation and islet cell isolation show promise for developing more successful methods of islet transplantation. Development of bio-engineered beta cells requires knowledge of the molecular pathways involved in glucose-regulated insulin secretion and effective methods of gene transfer. At the current time, the long-term complications of diabetes remain a major public health issue. Because current approaches to metabolic control are not sufficient for achievement of near euglycemia, new approaches are needed to prevent or ameliorate complications. Over the last decade, many biochemical mechanisms by which hyperglycemia may cause damage have been studied. These include increased polyol pathway activity and associated changes in intracellular redox state, increased diacylglycerol synthesis with consequent activation of specific protein kinase C isoforms, increased nonenzymatic glycation of both intra- 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. However, the molecular pathophysiology of altered protein function and gene expression leading to tissue injury is still unclear. The possible interrelationships between the various pathways have not been systematically explored. Different mechanisms may play a dominant role at different stages of disease or in different target tissues. In addition, despite epidemiological and clinical evidence of genetic determinants in the development of complications, very little is known about the identity or function of specific genes involved. This solicitation is intended to foster the development of interventions for modifying relevant pathways to prevent, reverse or delay the complications of diabetes. Recent advances in basic biomedical research have revolutionized our ability to study complex diseases such as diabetes. Application of new stratagems of molecular biology, genetics, immunology, cell biology, bioengineering and biophysics to diabetes research should lead to the identification of potential therapeutic strategies. This solicitation for pilot projects to develop and test these strategies is intended to enhance the development of new approaches to prevention and treatment of type 1 diabetes and its complications. Scope and Objectives R21 applications should focus on the prevention, cure or improved treatment of type 1 diabetes or its complications. Studies of etiology and pathogenesis may be submitted only if the focus is identification of new targets or strategies for therapy. Relevant topics listed below are examples and should not be construed as required or limiting. o Development and/or Testing of Strategies to Prevent or Reverse Type 1 Diabetes, o Identification of viral or environmental triggers and mechanisms by which such triggers initiate an autoimmune response o Capitalization on our present knowledge of beta cell antigens and/or epitopes and other components of the immune response leading to type 1 diabetes to develop methods to modulate this immune response to induce tolerance o Development of methods to regulate T cells autoreactive against beta cells o Development of methods to modulate co-stimulatory molecules and/or cytokines and thus alter the autoimmune response in type 1 diabetes o Identification of cellular and/or serum markers that can be used to identify high risk individuals, to track the activity of the autoimmune process and assess the utility of various strategies of immune modulation o Development of methods for measurement of beta cell mass or function that could be used as endpoints in studies of prevention or amelioration of type 1 diabetes o Development of non-human primate animal models of type 1 diabetes which closely parallel the human disease o Development and/or Testing of Mechanical or Cellular Approaches to Achieve Euglycemia o Identification of stem cells and/or methods for regulation of beta cell differentiation and growth o Improved techniques and programs for the isolation, maintenance and propagation of human islets or beta cells o Immunoalteration of beta cells/islets or of the immune response in an attempt to prevent autoimmune and host-versus-graft destruction of beta cells/islets o Identification of genes and their products that mediate and/or can abrogate autoimmune destruction or graft rejection o Development of immunobarrier technology to protect transplanted islets or engineered insulin-producing cells from autoimmune destruction or rejection o Genetic manipulation of beta cells or surrogate cells to replace the physiologic insulin secretory capacity that has been destroyed in type 1 diabetes o Evaluation in vivo of cellular approaches testing for graft rejection and/or autoimmune destruction o Development of bio-mechanical beta cell replacement therapies (glucose sensors, implantable pumps, bio-artificial pancreas) o Integration of sensor, control and delivery systems and creation of a true artificial pancreas, which may include examination of appropriate parameters for control of glycemia with insulin, delivered peripherally or intraperitoneally o Development of self-regulating implantable systems that are responsive to blood glucose levels o Develop and Test Strategies for Prevention and/or Therapy of Complications o Identification and functional characterization of genes influencing the development of long-term complications o Definition of the sequence of basic molecular or cellular processes leading to complications o Determination the sequence of events in the pathogenesis of hyperglycemia- induced injury so that potential sites for intervention can be identified o Identification of surrogate endpoints which can be used to track complications or identify patients at risk o Development of innovative pharmacological agents and interventions to prevent or halt the progression of long-term complications o Development of surrogate markers that could be used as endpoints for studies to test methods of prevention or amelioration of complications o Development of animal models useful to exploring the pathogenesis and therapy of complications of type 1 diabetes 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 have been 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 the following URL address: http://www.nih.gov.grants/guide/1994/94.03.18/notice-nih-guideline008.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 also may 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 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 IC staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent by the letter of intent receipt date listed in the heading of this RFA to: Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18G Bethesda, MD 20892 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: Joan_Harmon@NIH.GOV APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). Application 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: GrantsInfo@nih.gov. 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. 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, and five 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) REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and responsiveness by the participating Institutes. 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 reviewers 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 and according to the goals of this solicitation. (1) Significance: What is the potential of this work to lead to new methods of prevention and treatment of type 1 diabetes and its complications? 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: Expansion of the pool of talented investigators working in diabetes is a goal of this solicitation. 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 The 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 in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent 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. Since these applications are pilot and feasibility studies, applicants are not expected to have as extensive preliminary data as would be expected for a regular research application (R01). Compelling rational for a novel study or envisioned high impact of the work if successful could be sufficient justification in the absence of substantial preliminary data. Schedule Letter of Intent Receipt Date: March 1, 1999 Application Receipt Date: March 30, 1999 Peer Review Date: July 1999 Council Review: September 1999 Earliest Anticipated Start Date: September 1, 1999 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 are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18G Bethesda, MD 20892 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: Joan_Harmon@NIH.GOV Dov Jaron, Ph.D. Biomedical Technology National Center for Research Resources 6705 Rockledge Drive Room 6160 MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0775 FAX: (301) 480-3659 Email: BTAdir@ep.ncrr.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 Elaine Collier, M.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A20 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 Email: ec5x@nih.gov Gilman D. Grave, M.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B11 - MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX: (301) 480-9791 Email: GRAVEG@HD01.NICHD.NIH.GOV Dennis Mangan, Ph.D. Division of Extramural Research National Institute of Dental and Craniofacial Research Natcher Building, Room 4AN-32F Bethesda, MD 20892-6402 Telephone: (301) 594-2421 FAX: (301) 480-8318 Email: ManganD@de45.nidr.nih.gov Direct inquiries regarding fiscal matters to: Florence Danshes Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney diseases Building 45, Room 6AN-38A Bethesda, MD 20892 Telephone: (301) 594-8861 FAX: (301) 480-3504 Email: DanshesF@extra.NIDDK.NIH.GOV Louise Amburgey Office of Grants Management National Center for Research Resources 6705 Rockledge Drive Room 6086 MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0844 Email: louisem@ep.ncrr.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 Celeste Kerner Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Blvd. Room 4B32 Bethesda, MD 20892-7610 Telephone: (301) 402-6580 FAX: (301) 480-3780 Email: ck103k@nih.gov E. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17 - MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 Email: SHAWVERD@HD01.NIH.GOV Martin R. 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 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 (Diabetes, Endocrinology and Metabolism Research), No. 93.371 (Biomedical Technology), No. 93.867 (Vision Research), No. 93.387 (Heart and Vascular Disease), No. 93.855 (Immunology, Allergy, and Transplantation Research), No. 93.865 (Research for Mothers and Children) and No. 93.121 (Oral Diseases and Disorders Research Awards). 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, and 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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