Full Text DK-95-005 INFLAMMATORY BOWEL DISEASE AND OTHER AUTOIMMUNE DIGESTIVE DISEASES NIH GUIDE, Volume 24, Number 3, January 27, 1995 RFA: DK-95-005 P.T. 34 Keywords: Inflammation Digestive Diseases & Disorders Autoimmunity National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 24, 1995 Application Receipt Date: April 25, 1995 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 that elucidate the etiology of autoimmunity in gastrointestinal, hepatic, and biliary diseases using genetic and molecular biology approaches. Most notably advances could be generated in autoimmune digestive diseases such as inflammatory bowel disease (IBD), celiac disease, autoimmune hepatitis, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Also, the RFA encourages investigators to develop innovative molecular and genetic techniques and apply them via small clinical studies or pilot clinical trials in the clinical care of patients having one of the above mentioned autoimmune digestive diseases. 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, Inflammatory Bowel Disease and Other Autoimmune Digestive Diseases, is related to the priority area of 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, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, non-profit and for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for First INdependent Research Support and Transition (FIRST) (R29) awards. 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. The grantee organization and any proposed consortium must have the staff and facilities required for the proposed program. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The support mechanisms for this research will be the individual research project grant (R01) and the FIRST Award (R29). In addition, planning grants (R21) may be requested for small clinical or pilot studies. 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 other autoimmune digestive diseases. 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. New R01 applications should not request more than $160,000 in direct costs for the first budget period. Renewal R01 applications, if funded, will not be funded at more than 10 percent above their previous annual award level. FIRST Award applications must adhere to the R29 administrative guidelines (rev. 9/93) for eligibility, budget, and period of award. R21 awards may request no more than $50,000 direct costs for a one year period. 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 1995. 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. Although this program is provided for in 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. The National Institute of Allergy and Infectious Diseases (NIAID) is interested in basic and clinical research into the immune mechanisms underlying autoimmune gastrointestinal and liver diseases, including the inflammatory bowel diseases, ulcerative colitis and Crohn's disease, primary biliary cirrhosis, and autoimmune hepatitis. Applications that are of mutual interest are likely to be given secondary assignment to the NIAID in accordance with Division of Research Grants (DRG) referral guidelines. RESEARCH OBJECTIVES Background This solicitation requests applications for research projects that will elucidate the etiology and potential therapy of autoimmunity in gastrointestinal, hepatic, and biliary diseases using genetic and molecular biology approaches. A recent advance in the technology of site-directed mutation in vivo, commonly known as gene knock-out, has enabled investigators to create null mutations in virtually any cloned gene of interest. For digestive diseases with inflammatory manifestations, numerous genes are candidates for investigation into the molecular basis of autoimmunity. These include the family of cytokines, growth factors, cell adhesion molecules, and cellular receptors known to participate in systemic autoimmune disease with subsequent specific organ dysfunction as well as the specific autoantigens that have been identified in these diseases. Experimental observations of animals with specific null mutations and digestive tract disturbance would add significant insight into the etiology of autoimmune digestive diseases. The lack of such animal models for study has remained a major limitation for early diagnosis and targeted treatment of these disorders. Gene knock-out models could be complemented by transgenic animal models that provide information on gene regulation, development, and gene therapy. Examples of autoimmune digestive diseases in which notable advances could be made include inflammatory bowel diseases (IBD), celiac disease, autoimmune hepatitis, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). For the two most important IBDs, ulcerative colitis and Crohn's disease, there is a devastating attack on the gastrointestinal tract, obscure etiology, and unsatisfactory response to current therapy. Therefore, IBD is a chronic disease. Celiac disease is a small bowel disorder in which there is an immune mediated sensitivity to gliadin in foodstuffs that can only be controlled by life-long strict dietary restrictions. Autoimmune hepatitis is a disease of unknown cause that typically affects women and leads to end-stage liver disease. If not treated, and even with long term treatment using immunosuppressive agents, autoimmune hepatitis can lead insidiously to cirrhosis. PBC is a disease predominantly of middle-aged women that is characterized by immune destruction of small bile ducts in the liver causing chronic cholestasis and ultimately cirrhosis and hepatic failure. PSC, which is associated with ulcerative colitis, is another chronic cholestatic liver disease associated with diffuse inflammation of fibrosis of medium sized and large bile ducts that leads to end-stage liver disease. At present there are no specific therapies of proven benefit for PBC and PSC. Understanding the pathogenesis of these diseases would help design appropriate approaches to treatment or even prevention of these autoimmune conditions. In addition to the characterization of the unique genetic variation that results in autoimmune pathology of the gastrointestinal tract, hepatic and biliary systems, this solicitation also promotes applications with the following research aims: 1. In inflammatory bowel disease, to study the association of acute phase proteins, as well as IL-1, IL-6, TNF alpha, and other proinflammatory cytokines with the pathogenesis of chronic inflammation of the large bowel or gastrointestinal tract. 2. To elucidate therapeutic mechanisms related to reduced gastrointestinal inflammation or utilization of cytokine receptor antagonists, as well as other immune modulators. 3. To characterize the autoimmunity associated with gene knock-out mice with mutant TCR alpha and/or TCR beta expression or with MHC class II mutations as well as disrupted IL-2 and/or IL-10 expression. 4. In the hepatobiliary system, to use molecular techniques to characterize the autoantigens of autoimmune hepatitis, PBC, and PSC and to elucidate the role of cytokines, cytokine antagonists, adhesion molecules, chemotactic factors, receptors, and signal transduction molecules in the pathogenesis of these diseases. 5. In autoimmune chronic hepatitis, to explore the role of growth factors, cytokines, cytokine antagonists, adhesion molecules and chemotactic factors in chronic inflammatory liver disease. 6. To develop and apply innovative molecular and genetic techniques towards clinical care of patients with autoimmune digestive diseases. Applicants from institutions that have General Clinical Research Centers (GCRCs) 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 could be included with the application. STUDY POPULATIONS 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) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 24, 1995, 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, and 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 to: Robert Hammond, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8886 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. The form is available from most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Information describing the FIRST Award grant may also be obtained from these sources. The RFA label available in the 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 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 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 National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission of the application, two additional copies of the application must also be sent under separate cover to Dr. Robert Hammond at the address listed under LETTER OF INTENT. Applications must be received by April 25, 1995. 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 RFA 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. FIRST award applications without the required reference letters will be returned. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by a review group constituted by the NIDDK especially to review the applications submitted in response to this RFA. The review will be carried out in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the NIDDK national advisory council. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology 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 the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o where human subjects are included, 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. o availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or that provide augmentation of existing U.S. resources. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA The anticipated date of award is September 30, 1995. 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 may be directed to: Frank A. Hamilton, M.D., MPH Mucosal and Immunology Program National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-12B 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8877 Email: FAH@DVSGATE.NIDDK.NIH.GOV Thomas F. Kresina, Ph.D. Liver and Pancreas Programs National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-12A 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8871 Email: TFK@DVSGATE.NIDDK.NIH.GOV Tommie Sue Tralka DDDN Clinical Trials Program National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-12K 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8879 Email: TST@DVSGATE.NIDDK.NIH.GOV Inquiries regarding fiscal matters should be directed to: Mrs. Thelma Jones Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN-44B 45 Center Drive MSC 6600 BETHESDA, MD 20892 Telephone: (301) 594-8853 Schedule Letter of Intent Receipt Date: March 24, 1995 Application Receipt Date: April 25, 1995 Initial Review: June/July 1995 Second Level Review: September 1995 Anticipated Date of Award: September 30, 1995 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, last amended by Public Law 103-43, 42 USC 285c-8) 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 Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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