IMAGING PANCREATIC BETA CELL MASS, FUNCTION, ENGRAFTMENT OR INFLAMMATION Release Date: August 1, 2001 RFA: RFA-DK-02-002 National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. USE THE MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 (REVISION 5/2001) AVAILABLE AT PURPOSE This Request for Applications (RFA) is a reissue of RFA DK-99-018 Imaging Pancreatic Beta Cell Mass, Function, or Inflammation , and is intended to further stimulate the development of techniques or reagents leading to the ability to image or otherwise noninvasively detect pancreatic islet beta cells in vivo, and measure their mass, function, or evidence of inflammation, or to monitor engraftment of transplanted isolated pancreatic islets. Diabetes results when the insulin secretory capacity of the beta cell is lost or severely compromised. It is anticipated that research from funded projects will contribute to the eventual development of a clinical exam that can be used for monitoring disease progress and response to therapy in diabetics and in people strongly at risk for diabetes. Collaboration between researchers in imaging fields and beta cell biology or diabetology is strongly encouraged. A 1999 workshop entitled "Imaging the Pancreatic Beta Cell" was sponsored by NIDDK and Juvenile Diabetes Foundation International (JDFI). A report can be found at HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Imaging Pancreatic Beta Cell Mass, Function, Engraftment Or Inflammation , is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2010" at ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at This RFA will use the National Institutes of Health (NIH) research project grant (R01) and Pilot and Feasibility (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 4 years for the R01 and 2 years for the R21 mechanism. 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. The anticipated award date is Sept. 30, 2002. FUNDS AVAILABLE The NIDDK intends to commit approximately $1.0 million in FY 2002 to fund 3-5 new grants in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. An applicant may request a project period of up to 4 years using the R01 mechanism. All applications requesting $250,000 direct costs per year or less must use the modular budget format. R21 Pilot and Feasibility grant applications should request 2 years at up to $100,000 direct costs per year. These applications should propose innovative high risk, high yield research, and do not require the extensive preliminary data necessary for an R01 application. Although the financial plans of the NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Imaging technology has advanced rapidly in recent years, making it possible to image small or deep structures that have until now been impossible. It would be of great benefit to the diabetes community to be able to image the beta cells of the pancreatic islets. Insulin is produced in the pancreatic islet beta cell and released in response to a meal, to elevations in plasma glucose and certain other nutrients, and new evidence suggests a variety of other signals are involved. Diabetes results when insulin release is insufficient, and plasma glucose rises above normal. In type 1 diabetes, this occurs when the beta cells are selectively destroyed by an autoimmune process that involves lymphocyte infiltration. Early in the course of type 2 diabetes, as individuals become insulin resistant, beta cell mass increases to meet the demand for more insulin. The individual becomes diabetic when the beta cell mass and insulin production can no longer compensate for the increased need for insulin, and blood glucose begins to rise. Loss of beta cell mass may then occur as type 2 diabetes advances. Through major histocompatibility complex (HLA) typing and measurement of certain antibodies, it is now possible to identify those individuals that are at risk for developing type 1 diabetes. Those at risk for type 2 diabetes can be identified through family history and measurements of insulin resistance. However, little is known about the natural history of beta cell mass, turnover and cell lifetime, or the course of inflammation in diabetes. This is principally because the pancreas is a highly heterogeneous organ that is difficult to biopsy, and beta cell mass is only 1-2% of the organ. Insulin secretory capacity can be measured, but it is a poor reflection of beta cell mass. Recent advances in relatively noninvasive imaging techniques such as Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), other nuclear imaging techniques, and optical absorption or fluorescence spectroscopy and imaging, make it likely that a clinical exam to monitor beta cell number, mass, function, or lymphocyte infiltration/inflammatory activity can soon be established. This would allow high-risk individuals to be monitored prior to onset of diabetes, patients could be monitored over the course of their disease to determine the exact stage of their disease, and it would also allow monitoring responses to therapy. Type 1 diabetes is being successfully treated using pancreas transplantation, and researchers are now able to achieve insulin independence in patients by transplanting healthy, functioning isolated pancreatic islets into patients. In the course of evaluating this technique, it would be of great clinical benefit to be able to identify the location, number, viability, growth and function of these grafts, and to noninvasively monitor their response to immune modulating therapy using imaging. It is unlikely that resolution of any of the noninvasive, clinically useful imaging technologies is high enough at this point in time to visualize the pancreatic beta cell directly. However, a variety of cell and organ properties may be usefully exploited to provide contrast from surrounding acinar tissue. Antibodies or ligands for unique cell surface molecules could be tagged with MRI contrast agents, fluorescent dyes, or positron or gamma emitters. New screening technologies in functional genomics are helping to identify new genes and their products, which may be useful, beta cell-specific targets for molecular imaging. In particular, data produced by the NIDDK-sponsored Endocrine Pancreas Consortium in the project Functional Genomics of the Developing Endocrine Pancreas can be found at the EPConDB website, Type 1 diabetes is accompanied by a transient lymphocytic infiltration that results in beta cell destruction. Lymphocytes may be tagged with an imaging contrast agent for use in following the course of this inflammation. Unique aspects of beta cell metabolism can provide targets for PET studies, or MR spectroscopy could be used to measure concentrations of metabolites unique to the beta cell. Alternatively, optical imaging of enzyme activity may directly allow non-invasive evaluation of lymphocyte-based beta cell destruction. Blood flow through the microcirculation near the islet cells is increased in response to glucose and may provide a measure of the number and location of active beta cells. The capillaries feeding the islets are fenestrated, and diffusion of water, macromolecules, or contrast agents may be altered enough near these special cells to be exploited for imaging them. Type 2 diabetes is often accompanied by large deposits of amyloid fibrils (IAPP, islet amyloid polypeptide) in and around the beta cells, which may contribute to their destruction late in the disease. These macromolecular deposits may be a target for imaging. Scope and Objectives The objective of this initiative is to support the development of imaging techniques and reagents that could be used to measure beta cell mass, function, or inflammation with the hope that these technologies can aid in diagnosis and treatment of diabetic and prediabetic patients in the clinic. A 1999 workshop entitled "Imaging the Pancreatic Beta Cell" was sponsored by NIDDK and Juvenile Diabetes Foundation International (JDFI). A report can be found at or obtained from the program staff listed at the end of this document, and should be consulted in conjunction with this announcement. Projects submitted to this initiative may describe research aimed either at developing some imaging technique for this application, identifying unique aspects of the beta cell that could be exploited for imaging, or the development of new contrast agents that can be targeted specifically to the beta cell. This initiative can be used to support research in animal models or in human subjects. Because of the highly specialized nature of this work, imaging experts, chemists, engineers, beta cell and diabetes researchers and clinicians are encouraged to collaborate. Areas of research emphasis include: o Development of specific techniques or contrast agents that can be used with a clinical imaging modality to visualize pancreatic beta cell mass or number. These include tagged antibodies to the beta cell surface, ligands for receptors specific to the beta cell, or agents whose contrast properties are "unmasked" by beta cell enzymes. o Projects designed to identify specific beta cell surface markers or create monoclonal antibodies to beta cell surface molecules. o Development and evaluation of non-radioactive labeling for tracer imaging. o Development of imaging assays of beta cell function in response to glucose or other insulin secretagogues. o Development of angiographic, perfusion and diffusion techniques for visualizing changes in blood flow near islets due to functional activation. o Identification, characterization and development of transgenic models with beta cells enhanced for imaging using GFP, luciferase or beta- galactosidase, which might be useful as controls, for cell mass assessment during the course of experimental diabetes, and to determine beta cell lineages throughout development. o Development of methods to image trafficking of immune cells (T cells, macrophages) and immune cell enzymatic activity in order to monitor inflammation and destruction of the beta cellin type 1 diabetes. o Evaluation of whether or not the IAPP inclusions in the pancreatic islets in type 2 diabetes can be visualized. o Development of methods to monitor the location, mass, and function of engrafted islet cells after transplantation. Also, development of methods to assess the presence of local inflammation around engrafted islets. SPECIAL REQUIREMENTS Collaborations between experts in appropriate disciplines are highly encouraged, and money for travel should be specifically requested if necessary. Successful applicants will be expected to meet together yearly in Bethesda, MD, to share results and information. Travel funds should be requested for this meeting. 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 are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (, a complete copy of the updated Guidelines are available at The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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: Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: Applicants may wish to place data collected under this RFA (PA) in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit, by February 15, 2002, 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 plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at is to be used in applying for these grants, with modular budget instructions beginning on page 13 of the application instructions. The RFA label available in the PHS 398 (rev. 5/01) 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. The sample RFA label available at: has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and 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, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. 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 Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. If the application is not responsive to the RFA, NIDDK or CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in the competition with unsolicited applications at the next review cycle. 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 the review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NIDDK Advisory Councils. 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. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) 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? (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 methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (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 Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. 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. Schedule Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 Peer Review Date: July 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 30, 2002 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 concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Maren R. Laughlin, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 6101 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8802 FAX: (301) 480-3503 E-mail: Direct inquiries regarding fiscal matters to: Denise Payne Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 733 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8845 FAX: (301) 480-3504 E-mail: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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