Full Text DK-93-15 PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE AND CELIAC DISEASE NIH GUIDE, Volume 22, Number 1, January 8, 1993 RFA: DK-93-15 P.T. 34 Keywords: Digestive Diseases & Disorders Immunology Genetics Biology, Cellular Biology, Molecular Epidemiology National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 24, 1993 Application Receipt Date: April 21, 1993 PURPOSE This Request for Applications (RFA) invites new as well as experienced investigators working in the areas of gastroenterology, epidemiology, immunology, physiology, molecular and cell biology and genetics to submit research project grant applications in the area of autoimmune gastrointestinal diseases including ulcerative colitis, Crohn's disease and celiac disease. Applications are encouraged from any interested investigators regardless of their prior record of grant support. HEALTHY PEOPLE 2000 The NIH 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, Pathogenesis of Inflammatory Bowel Disease and Celiac Disease, 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 Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, D.C. 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, non-profit and for-profit organizations, whether public or private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal Government. Among a team of applicants, one institution must be proposed as the lead organization to serve as the Grantee Institution and assume responsibility for the fiscal and programmatic conduct of this project. Other members of the team should be proposed based on individual consortium agreements (subcontracts). The grantee organization and any proposed consortium must have the staff and facilities required for the proposed program. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The support mechanisms for this research will be the individual research grant (R01) and the First Independent Research Support and Transition (First) Award (R29). This is a one-time solicitation. Subsequent unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to customary peer review procedures. This RFA will provide the opportunity for investigators to establish support for periods up to five years for meritorious research projects designed to investigate the cause, natural history and treatment of Inflammatory Bowel Disease and celiac disease. This RFA is intended to support primarily new applications; however, applications for continuation of currently funded projects will be considered if they meet the objectives of this RFA. R01 awards are expected to average approximately $200,000 per year in total costs. Note: Foreign institutions are not eligible for FIRST awards. FUNDS AVAILABLE The NIDDK plans to support approximately 10 to 12 applications submitted in response to this solicitation. Total costs of $2 million (direct and indirect costs) for this program have been included in the financial plans for fiscal year 1993. The number of awards to be made is dependent upon receipt of a sufficient number of applications of high scientific merit and upon availability of funds. Applicants for an R01 award must limit their request to not more than $160,000 direct costs for the initial budget period, and normal biomedical inflation increments in future years will be allowed. Applicants for FIRST awards must limit their requests to $350,000 total direct costs across 5 years. Although this program is provided for the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Inflammatory Bowel Disease (IBD) is a general term given to two diseases, ulcerative colitis and Crohn's disease, that together are major causes of morbidity and mortality from gastrointestinal disorders. It is estimated that 2 million Americans are affected by IBD, many of them in the younger age groups. Ulcerative colitis and Crohn's disease have many similar clinical and pathological features and are considered to be autoimmune in etiology. However, the pathogenesis of IBD is complex and not well understood. Ulcerative colitis and Crohn's disease appear to be the result of a combination of factors including genetic predisposition, alterations in the mucosal immune system and exposure to unknown, triggering exogenous factors, such as intestinal microbes, toxins, food substances or drugs. As for most autoimmune diseases, the specific etiology and pathogenesis of both ulcerative colitis and Crohn's disease remain unclear. Current therapies for IBD are helpful in ameliorating the symptoms and complications of these diseases but are, in general, unsatisfactory and do not provide a specific cure or prevent or alter the eventual natural history of disease in the majority of patients. Celiac disease, also known as non-tropical sprue and gluten-sensitive enteropathy, is another mucosal disease of the gastrointestinal tract that is believed to be autoimmune in etiology. Celiac disease affects approximately a quarter million Americans and usually presents with clinical symptoms during infancy or childhood. Celiac disease is triggered by ingestion of gluten products from wheat, rye, barley and possibly oats, but it also has a major genetic component. Nevertheless, the primary pathogenesis of celiac disease remains obscure. It is not clear how gluten interacts with the intestinal mucosa and induces injury, what components of gluten are responsible for the injury, what genetic defect(s) or abnormal gene(s) predispose to the disorder, or what other exogenous exposures induce this condition. Celiac disease represents a paradigm for autoimmunity and autoimmune diseases in requiring a genetic background, immunologic disturbance and exogenous exposure (gluten) for its expression. At present, the clinical features of celiac disease can be resolved by avoidance of gluten in the diet. However, the dietary restrictions for treatment of celiac disease are challenging and require life-long adherence. Furthermore, there remains an increased incidence of gastrointestinal lymphoma among patients with celiac disease. The NIDDK believes that an intensified research effort into defining the pathogenesis of IBD and celiac disease will help in the prevention and therapy of these important gastrointestinal diseases. The NIDDK encourages collaborative research among the multiple disciplines of gastroenterology, immunology, epidemiology, physiology, molecular, structural and cell biology and genetics to help elucidate the etiology and pathogenesis of IBD and celiac disease. The NIDDK especially encourages new investigators from different fields of research to apply cutting edge research technology and innovative approaches to the understanding of these autoimmune gastrointestinal diseases. Institutions that have demonstrated experience in both clinical and basic science research will be considered most favorably for support. Applications should be directed at the information needed to fill gaps in our knowledge concerning the etiology of ulcerative colitis, Crohn's disease and celiac disease. Examples of possible topics relevant to this RFA include: o the role of the mucosal immune system and its immunoregulation in gastrointestinal inflammation characteristic of IBD and celiac disease; o the role and status of inflammatory mediators, the cytokine system and adhesion molecules in IBD and celiac disease; o the nature of the autoimmune reactions characteristic of IBD and celiac disease including definition of the autoantigens and the fine specificity of autoantibodies that are detected in patients with IBD and celiac disease; o genetic markers and specific gene products associated with IBD and celiac disease and in particular the molecular genetics of the major histocompatibility complex in these disorders; o epithelial cell biology and its disturbance in gastrointestinal inflammation characteristic of IBD and celiac disease; o the role of luminal bacterial flora and viral infections in IBD and celiac disease; and o the epidemiology of IBD and celiac disease with particular attention to special populations and risk factors for development of these diseases as well as their complications such as sclerosing cholangitis in ulcerative colitis and lymphoma in celiac disease. 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. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator could be included with the application. STUDY POPULATIONS - SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionally affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (Rev. 9/91) in Item 4 (Research Design and Methods) of the Research Plan and summarized in Item 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations; i.e., Native Americans (including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention [and preventive strategies], diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned without review. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed and the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. 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 is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NIDDK staff to estimate the potential review workload and to avoid possible conflict of interest in the review. The letter of intent is to be sent by February 26, 1993 to: Robert Hammond, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 605 Bethesda, MD 20892 Telephone: (301) 496-7083 FAX: (301) 402-1277 APPLICATION PROCEDURES The research grant application form PHS-398 (revised 9/91) must be used in applying for these grants. The form is available from most institutional business offices or from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892; (301) 496-7441. Information describing the FIRST Award grant may also be obtained from these sources. The RFA label available in the 9/91 revision of PHS 398 application form must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your 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 2a of the face page of the application form and check the YES box. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package to: DIVISION OF RESEARCH GRANTS Westwood Building, Room 240 National Institutes of Health Bethesda, MD 20892 At the time of submission, two additional copies of the application should also be sent under separate cover to Dr. Robert Hammond, at the address shown above. Applications must be received by April 21, 1993. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, it is allowable to submit the same project as both an R01 (or R29) and as a component project of a program project. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed. Such applications must not only include an introduction addressing the previous critique but also be responsive to this RFA. For investigators applying for support through the FIRST award mechanisms (R29), three letters of references must be submitted with the application. An applicant submitting a revised application in response to this RFA must again submit reference letters. Note: Foreign institutions are inelgible for the R29 award. REVIEW CONSIDERATIONS Upon receipt, applications will be initially reviewed by the Division of Research Grants (DRG) for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the program requirements and criteria stated in the RFA is an NIDDK staff function. If the application is not responsive to the RFA, NIDDK staff will contact the applicant to determine whether it should be returned to the applicant, or whether it should be held until the next regular receipt date and reviewed in competition with all other research project applications. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NIDDK. In cases where the number of applications is large compared to the number of awards to be made, a preliminary scientific peer review may be conducted and applications withdrawn from further competition when they are not competitive for the award. The NIDDK will notify the applicant and institutional official of this action. Those applications judged to be competitive will be reviewed for scientific and technical merit in accordance with the usual NIH peer review procedures by an initial review group specifically convened for this RFA. Following this review, the applications will be given a secondary review by the National Diabetes and Digestive and Kidney Diseases Advisory Council unless not recommended for further consideration by the initial review group. Review criteria for RFAs are generally the same as those for unsolicited research grant applications. o scientific/technical merit criteria specific to the objectives of the RFA; o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; o availability of resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; and o if an application involves activities that could have an adverse effect upon humans, animals, or the environment, the adequacy of the proposed means for protecting against or minimizing such effects. AWARD CRITERIA The anticipated date of award is September 30, 1993. Applications will compete for available funds with all other recommended applications submitted in response to this RFA. The following will be considered in making funding decisions: Quality of the proposed projects as determined by peer review, availability of funds, and program balance and scientific interrelationships among the proposed projects. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. Inquiries regarding programmatic issues should be directed to: Frank A. Hamilton, M.D., MPH Mucosal and Immunology Program Director, NIDDK Westwood Bldg, Room 3A16 National Institutes of Health Bethesda, MD 20892 / Tel. 301 496-7821 Inquiries regarding fiscal matters should be directed to: Mrs. Thelma Jones Grants Management Specialist, NIDDK Westwood Building, Room 649C National Institutes of Health Bethesda, MD 20892 / Telephone: (301) 496-7467 SCHEDULE: Letter of Intent: February 26, 1993 Application Receipt: April 21, 1993 Initial Review: June/July 1993 Second Level Review: September 1993 Anticipated Award: September 30, 1993 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. 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 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. .
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