and Human Services (HHS)
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HEMOCHROMATOSIS AND DIABETES MELLITUS Release Date: February 9, 2000 PA NUMBER: PA-00-055 National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung and Blood Institute THIS PA USES THE "MODULAR GRANT" AND JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI) invite investigator- initiated research grant applications to study the molecular mechanisms underlying the pathogenesis of diabetes mellitus in hemochromatosis and other forms of iron overload, and to encourage clinical studies leading to a better understanding of the development of diabetes in patients with iron overload. 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 PA, The Role of Growth Factors in the Development of Diabetes Complications, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000 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 This PA will use the National Institutes of Health (NIH) research project grant (R01) and Exploratory/Development Research Grant (R21) award mechanisms. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators, 2) allow exploration of possible innovative 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. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program). NHLBI will accept assignment only of RO1 applications. Applicants interested in submitting R21 applications may wish to seek guidance from Institute Program Directors listed under INQUIRIES. This PA will use the modular grants application and award process. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 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 Institute staff. Refer to instructions under APPLICATION PROCEDURES, below. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The NIH Grants policy statement applies to these awards. RESEARCH OBJECTIVES Background Hereditary hemochromatosis is the most common genetic disorder known in the United States. As much as 10 percent of the population is heterozygous for this condition, and the homozygous state is believed to affect as much as 0.5 percent of the population, or more than one million people. In affected individuals, inappropriately increased absorption of iron may result in its progressive accumulation in the liver, heart, pancreas and other organs, eventually producing hepatic cirrhosis, cardiac failure, diabetes mellitus, arthritis, gonadal dysfunction and other disorders. The identification of the gene, now designated as HFE, that is mutated in most patients with hereditary hemochromatosis has been a major advance that has resulted in a diagnostic genotypic test for this form of iron overload. Population studies suggest that the disorder is greatly under-diagnosed. Diabetes mellitus is a major complication of hemochromatosis and virtually all the secondary manifestations of diabetes may develop, including retinopathy, nephropathy, neuropathy and vascular disease. At the basic science level, the molecular mechanisms underlying the pathogenesis of diabetes mellitus in all forms of iron overload remain obscure. Iron-induced, free radical mediated damage to the pancreatic beta- cell has been postulated but careful studies in this area are lacking, hindered, in part, by the lack of a suitable animal model. Some data suggest that insulin resistance and beta-cell dysfunction in patients with iron overload develop well before insulin deficiency and are still reversible with iron depletion. Iron overload as a potentially reversible cause of diabetes needs more careful examination. Clinically, the discovery of the gene, HFE, responsible for most cases of hereditary hemochromatosis, has revolutionized both the understanding and diagnosis of this disorder and created new opportunities for studies of diabetes as one of the major complications of the disease. In patients with hemochromatosis, the development of diabetes is an irrevocable step in disease progression that leads to premature death, even if the excess iron is subsequently removed. Conversely, hereditary hemochromatosis is a preventable cause of diabetes mellitus. If patients are identified before the development of glucose intolerance, removal of the excess iron can prevent the subsequent development of diabetes. Because of the importance of hemochromatosis as an often unrecognized cause of diabetes and because of the significance of diabetes as a critical complication in hemochromatosis, clinical studies are needed. These may include (i) determination of the prevalence of hereditary hemochromatosis as an undiagnosed cause of diabetes mellitus, (ii) determination of the prevalence of HFE mutations (both heterozygous and homozygous) in patients with diabetes, (iii) development of new strategies for the management of diabetes in patients with hemochromatosis. Objectives and Scope Appropriate topics for investigation would include, but are not limited to: o Epidemiological investigations of the relationship between body iron burden, HFE mutations, especially Cys282Tyr and His63Asp, glucose tolerance, insulin sensitivity and diabetes. o Elucidation of the cellular and molecular mechanisms underlying the pathogenesis of diabetes mellitus in (or associated with) iron overload disorders. o The potential role of iron-induced, free radical or lipid peroxidation- mediated damage to the pancreatic beta-cell and to hepatocytes. o Effects of increased body iron burden on insulin resistance and glucose transporter function in several insulin target cells: e.g., muscle, adipocyte, hepatocyte. A number of reports suggest that increased iron leads to insulin resistance but the mechanisms responsible for this resistance are obscure. o Investigations of differential gene transcription/translation in beta cells, hepatocytes and enterocytes caused by exposure to elevated iron. o Investigation of the effectiveness of iron chelation therapy in preventing or reversing iron-overload mediated diabetes. o Investigations of ceruloplasmin status vs. the incidence of diabetes. It is clear that patients with aceruloplasminemia get diabetes and that this condition is associated with parenchymal iron accumulation, but it is not known whether quantitative (or functional) variations in ceruloplasmin might have similar but less obvious effects. o Studies of the natural history of diabetes associated with hemochromatosis. o Since individuals at risk can be identified early, serial metabolic characterizations before and early in the disease to define the initial events in progression to diabetes are of interest. o Examination of insulin resistance to learn if it is caused by hemochromatosis or if people with both conditions are more likely to progress to diabetes. o Study of the extent to which diabetes is reversible when iron overload is corrected. o Development of suitable animal models for study of diabetes of iron overload. 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 new 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 was 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.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 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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or 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. Applicants planning to submit an investigator-initiated new (type 1) competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact NIH program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the staff that the NIH will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. SPECIAL INSTRUCTIONS FOR MODULAR GRANT APPLICATION PROCEDURES Budget Instructions Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The program announcement 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 the signed, original, single-sided application, including the Checklist, along with five signed photocopies and five collated sets of appendix materials 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) The Center for Scientific Review (CSR) will not accept any application in response to this PA 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 already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established NIH referral guidelines. 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, reviewer 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. 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? 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. AWARD CRITERIA The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review, o Availability of funds, o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. David G. Badman Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-13C MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: db70f@nih.gov Dr. Charles M. Peterson Blood Diseases Program National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0051 FAX: (301) 480-0868 Email: PetersoC@gwgate.nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Ms. Aretina Perry-Jones Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-38B, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8862 FAX: (301) 480-3504 Email: PerryA@extra.niddk.nih.gov Ms. Jane Davis Division of Extramural Activities National Heart, Lung, and Blood Institute 6701 Rockledge Drive MSC 7950 Bethesda MD 20892-7950 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: davisj@gwgate.nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Assistance Nos. 93.848 and 93.847. 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 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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