CELLULAR AND MOLECULAR APPROACHES TO ACHIEVING EUGLYCEMIA NIH Guide, Volume 26, Number 38, November 21, 1997 RFA: DK-98-007 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Center for Research Resources National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development National Institute on Aging Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Center for Research Resources (NCRR), the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHD), and the National Institute on Aging (NIA) invite investigator- initiated research grant applications to develop therapies to achieve euglycemia in people with type I diabetes. These applications could include: islet and beta cell transplantation; engineering of regulated insulin secretion in non-beta cell surrogates; hematopoietic stem cell therapy for the induction of tolerance; or development of technologies to preserve beta cell function and stimulate beta cell regeneration. Particular emphasis should be placed on the development of clinically applicable technologies. This Request for Applications (RFA) is intended to stimulate the application of advances in cell biology, bioengineering, immunology, molecular biology, gene therapy and transplantation to the development of safe and effective therapies to regulate glucose homeostasis in humans. Collaborative efforts linking expertise in these disciplines to expertise in diabetes are strongly encouraged. Two-year pilot and feasibility applications and interactive research projects, which will support the efforts of several independent investigators working in a collaborative manner, are available within this RFA. It is anticipated that results obtained from studies supported by this RFA will aid in the development of improved therapies for the treatment of type I diabetes mellitus. 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, Cellular and Molecular Approaches to Achieving Euglycemia, 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: https://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 in direct costs per year for any year should consult with the NIDDK Program Official listed under "INQUIRIES" at an early opportunity. Applicants for R01 mechanism 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, $5 million will be committed to fund applications submitted in response to this RFA. It is anticipated that 18 to 20 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 Diabetes mellitus affects approximately 16 million people in the United States. Individuals with type 1 diabetes mellitus have lost their ability to produce insulin due to immune system-mediated destruction of the insulin producing beta cells of the pancreas. On September 4 and 5, 1997, the NIH sponsored a conference entitled "Diabetes Mellitus: Challenges and Opportunities." This conference identified research opportunities in several areas, one of the most important being the need for innovative therapies for diabetes. It was noted that intensive treatment of type 1 diabetes, although effective in improving long-term outcome, is difficult to implement for many patients and does not achieve euglycemia. The level of glycemic control achieved using currently available intensive treatment methods is at best 4-5 standard deviations above the mean value for the nondiabetic population, as measured by glycated hemoglobin (HbA1c). Intensive therapy is also limited by the accompanying increased frequency of severe hypoglycemia and weight gain, resulting in an increasing prevalence of overweight patients with type 1 diabetes. Finally, currently available intensive therapy is particularly problematic in children and adolescents due to difficulties in getting them to comply with current treatment regimens. This is especially troublesome since current clinical data support early intervention as being most effective treatment strategy. Thus, the results of the Diabetes Control and Complications Trial indicate that maintenance of near normal glycemic levels can reduce and delay the onset of the devastating complications of diabetes. Therefore, establishing methods to achieve and maintain euglycemia will have enormous impact on the health and quality of life of individuals with diabetes. Scope and Objectives Although the ultimate research goal is to prevent the onset of type 1 diabetes, investigators are currently developing approaches and technology to modulate blood glucose levels in patients with diabetes and to restore insulin-producing capacity through transplantation of the whole pancreas, or of islets from the pancreas. Today, the only method that offers normal blood glucose levels is pancreas transplantation. Several decades ago, islet transplantation was proposed in the hope of reducing the need for difficult surgical procedures by allowing intravenous injection of islets. Initial animal studies on islet transplantation were encouraging, but subsequent research using larger animals and humans resulted in lower success rates as defined by exogenous insulin independence. Unfortunately, the initial promise held out for islet cell transplantation has not been realized. Thus, of the 270 adult islet transplants performed by the end of 1995 in patients with type 1 diabetes, only ten percent of recipients did not require insulin injections for more than one week, and only five percent remained off exogenous insulin for more than one year. In light of these results, studies are needed to better understand what treatment regimens would allow successful islet transplantation using the least amount of immunosuppression, thereby minimizing the toxicity to the islet. For example, corticosteroids, a mainstay of immunosuppressive regimens for solid organ transplantation, interfere with the normal beta cell function to release insulin in response to elevated blood sugar levels. In addition, the recurrence of autoimmune- mediated destruction of transplanted beta cells is problematic, and many researchers are pursuing studies to abrogate the underlying autoimmunity that has led to type 1 diabetes. While the "gold standard" for transplant success has been insulin independence, clinicians are observing a beneficial effect of islet transplantation even in recipients who have not achieved insulin independence. These patients require less exogenous insulin and show an improvement in metabolic control, which equates to fewer episodes of severe hypoglycemia. This effect may also lower the risk of long-term complications. Considerable knowledge has accrued from these early studies, including: improved procedures for handling the donor pancreas to optimize islet survival; improved methods for preparing large quantities of islets; the development of standardized solutions of enzymes to dissociate the islets from the other pancreatic tissue; pre-transplant treatment methods to reduce rejection; cryopreservation procedures; and evidence of the detrimental effects of immunosuppressive therapy on islet function and survival. Other beta cell replacement strategies include bioengineered beta cells, beta cells grown in continuous or permanent culture to expand the number available for transplantation, and animal islets. Bioengineered beta cells could be non-beta cells that would be transfected with specific genes to mimic beta cell function, could be "real" beta cells engineered to enhance engraftment or prevent rejection, or could be a combination cell which functions to release insulin in response to glucose and prevents graft rejection. To pursue and evaluate such strategies, it will be critical to establish those beta cell components that are required for glucose-regulated insulin secretion. These functional components would, of course, include the internal beta cell machinery, but may also include interactions among beta cells and interactions between beta cells and the extracellular matrix. Animal islets, while offering an ample supply of islets, present additional risks, such as the transmission of animal diseases to humans and accelerated immune rejection. Another potentially worthwhile approach to achieving euglycemia involves immune isolation in conjunction with beta cell replacement procedures under study. There are several methods to achieve immune isolation, including implantation in an immune-privileged site; encapsulating in an immune protective membrane; and co-transplantation of beta cells with, for example, transfected myoblasts secreting agents (TNF or Fas-L) to induce apoptosis of the invading cytotoxic lymphocytes. All of these methods require further development and evaluation. In addition to procedures to isolate insulin-producing cells from the immune system, novel approaches should be developed to eliminate the need for general immunosuppressive therapies to prevent islet rejection. Such an intervention might be co-administration of donor hematopoietic stem cells to induce tolerance. Informed assessment of the efficacy of the various approaches to achieving euglycemia will require noninvasive methods, such as PET, MRI, or NMR, for measuring beta cell mass, the degree of autoimmune destruction, and/or islet cell rejection. Development of these technologies may require marking the beta cell to allow detection. Application of these technologies to diabetes will be important to assess transplant outcome and enhance understanding of the pathogenesis of type 1 diabetes. The scope of this RFA includes methods to enhance the supply and sources of insulin-producing cells; identification of the cellular components necessary for glucose-responsive insulin secretion; development of methods to protect insulin- producing cells via immunoisolation or immunomodulation/tolerance induction; the application of in vivo or in vitro gene delivery systems; development of noninvasive procedures to measure islet/beta cell mass/function or destructive disease processes; and the establishment of hematopoietic stem cell therapies for immunomodulation. Relevant topics for study listed below are examples and should not be construed as required or limiting. o Determination of the optimal site for islet engraftment to minimize the immune response and maximize graft function o Determination of the optimal number of islets necessary to ensure engraftment, most efficiently o Establishment of methods to completely abrogate the non-specific inflammatory response to infused islets o Assessment of how to prevent autoimmune destruction of the transplanted isles, using molecular or cellular approaches to achieve long-term islet survival o Identification of genes and their products that regulate glucose-stimulated insulin release, including those involved in glucose recognition, stimulus- secretion coupling mechanisms and exocytic mechanisms o Identification of genes and their products that can abrogate allogeneic or xenogeneic rejection processes o Identification of genes and their products that can abrogate autoimmune destruction o Development of immunoisolation materials to minimize non-specific inflammatory damage and shedding of antigen from the internal islets that would initiate an immune response and rejection, while permitting transport of necessary cell growth-promoting factors, nutrients and oxygen o Development and evaluation of immunosuppressive regimens to optimize patient safety and promote islet allograft survival o Application of gene-therapy, knock-out and anti-sense methodologies to promote islet cell engraftment and long- term survival, including but not limited to affecting expression of CD40/CD40L, Fas/FasL, cytokines, adhesins, and other immune system regulatory molecules o Optimization of tolerance induction protocols that would allow indefinite islet survival o Evaluation of xenogeneic islet transplantation with regard to hyperacute rejection and safety issues, including transmission of non-human infectious agents to human recipients o Development of noninvasive technologies to measure islet/beta cell mass/function, disease status and/or progression o Establishment of novel islet or surrogate cell transplant protocols incorporating innovative technologies to prevent graft rejection and maintain glucose-stimulated insulin secretion o Develop animal models and/or in vitro models of ductal cell hyperplasia and islet regeneration for the identification of cytokines and growth factors which stimulate this process o Examination of molecular and cellular mechanisms underlying age-related changes in islet and beta cell function in older subjects from the perspective of both a) cellular response to extracellular signals and b) age-related alterations in hormonal and cytokine milieu o Elucidation of the mechanism by which immunological memory against beta cell antigens persists in type 1 diabetes long after complete destruction of the beta cell mass o Determination of the whether significant insulin gene expression can be induced by cytokines, growth factors, and transcription factors in surrogate beta cells 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 rational 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 if contains allows NIH 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 Disease 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 301/710-0267, 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 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 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 Disease 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 whereby only those applications deemed to have high scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council of the assigned Institute or Center. 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 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 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. 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: Joan T. Harmon, Ph.D. Diabetes Research Section National Institute of Diabetes and Digestive and Kidney Diseases 45 CENTER DRIVE, Room 5AN-18G MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8808 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 Stephen M. Rose, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A14 Bethesda, MD 20892-7640 Telephone: (301) 496-5598 FAX: (301) 402-2571 EMAIL: sr8j@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 Frank Bellino, Ph.D. Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: bellinof@gw.nia.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 E-mail: dixonn@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 Laura Eisenman Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B23 Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Fax: (301) 480-3780 Email: le55d@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 Robert Pike Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 email: pikeb@gw.nia.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 Metabolism Research), No. 93.855 (Immunology, Allergy, and Transplantation Research), No. 93.865 (Research for Mothers and Children), 93.866 (Aging Research) and 93.371 (Biomedical Technology). 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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