MOLECULAR AND GENETIC MECHANISMS IN PANCREATITIS Release Date: January 14, 1999 PA NUMBER: PA-99-040 P.T. National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The Division of Digestive Diseases and Nutrition and the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) wish to encourage experienced and new investigators to pursue basic and clinical investigations into the molecular biology and molecular genetics of acute and chronic pancreatitis as well as pancreatic insufficiency associated with cystic fibrosis. Studies are sought to expand the recently reported observations that some patients with pancreatitis have mutations in CFTR, the gene that causes cystic fibrosis. Coupled with the recently identified gene for hereditary pancreatitis and a possible association of pancreatitis with mutations in the alpha-1-antitrypsin gene, further studies are warranted on the molecular and genetic mechanisms of acute and chronic pancreatitis. Basic studies include the molecular regulation or biological mechanisms of mutated genes in the generation of pancreatitis as well as the generation of animal models of pancreatitis and, particularly, organ-specific transgenic or knock-out mice that exhibit acute or chronic pancreatic abnormalities. Clinical and epidemiological studies are also sought that increase our knowledge of the risk factors, means of detection and diagnosis, natural history and prognosis, prevention and treatment of pancreatitis. These studies could utilize the recent advances that identify mutated genetic loci in patients with pancreatitis. 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 Program Announcement (PA), MOLECULAR AND GENETIC MECHANISMS IN PANCREATITIS, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html 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 This PA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism as well as the Exploratory/Developmental Grant (R21) award mechanism. The total project period for a research project grant (R01) application submitted in response to this PA may not exceed 5 years. The Exploratory/Developmental Grant (R21) award provides funds for exploratory research projects (maximum $100,000 per year for two years). Applications for the R21 Award should stress the innovative and exploratory nature of the proposed research. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. RESEARCH OBJECTIVES Pancreatitis is a syndrome that is characterized by recurrent attacks of pain associated with inflammation and damage to the pancreas. Relapsing or chronic pancreatitis can lead to exocrine and endocrine pancreatic insufficiency. Major causes of pancreatitis are alcohol and cholelithiasis. However, a large percentage of cases are idiopathic, in that no causative agent can be found despite extensive investigation. Recently, a hereditary component has been elucidated with the identification and cloning of a "hereditary pancreatitis" gene. Mutations in the pancreatic trypsinogen gene can cause a loss of auto- regulation of the pancreatic digestive enzymes and subsequent auto-digestion of the pancreas by the potent proteases that the organ produces. Pancreatic insufficiency is also seen in most patients with cystic fibrosis. These patients have progressive pancreatic damage as a result of ductal inspissation that leads to early clinical manifestations of maldigestion due to pancreatic insufficiency. Individuals with more severe forms of the disease who have pancreatic insufficiency have a shorter median survival of 29 years compared to cystic fibrosis patients with milder forms of the disease with pancreatic sufficiency (56 years median survival). The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has resulted in significant progress in the understanding of the wide spectrum of abnormalities comprising cystic fibrosis. More than 800 putative mutations of the CFTR gene have been identified and attempts have been made to elucidate the relationship between genotype and the phenotype of the disease including the pancreatic manifestations. CF patients with pancreatic insufficiency generally have two alleles associated with severe abnormalities. Mutations associated with severe disease account for approximately 92% of known mutant CFTR chromosomes, and thus approximately 84% of patients will have two alleles associated with severe disease with pancreatic insufficiency. Recent studies have reported that 6-37% of patients with idiopathic pancreatitis have a CFTR mutation on at least one chromosome. Some individuals with "idiopathic" pancreatitis were identified with two mutant CFTR alleles but did not have lung disease of typical cystic fibrosis. Genetic testing of patients with pancreatitis has identified individuals with other genetic abnormalities, including an abnormal alpha-1-antitrypsin phenotype with low serum protein level. Thus, genetic screening of patients with pancreatitis has resulted in identifying numerous abnormal genes possibly related to the pancreatic injury. The alleles when homozygous are associated with severe pancreatic disease. Thus, these studies have resulted in the possibility of a gene dosage effect in the etiology of some forms of idiopathic pancreatitis. This PA requests both basic and clinical studies that address the identification of genetic factors predisposing individuals to pancreatitis. Such studies would include but are not limited to research specific aims that promote: o Genetic screening studies that identify gene mutations in candidate genes or their regulatory elements associated with pancreatic structural or functional abnormalities; o The identification of biologic or molecular mechanisms of pancreatic injury associated with the identification of mutant alleles; o The generation of novel animal models of pancreatitis or abnormal pancreatic function by expression of mutant genes associated with pancreatic disease; and o Identification of other genetic and environmental factors that influence the development and course of pancreatitis in genetically susceptible individuals. 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 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, Vol. 23, No. 11, March 18, 1994 available on the web at the following URL address: http://www.nih.gov/grants/guide/notice-files/not94-105.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://www.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may 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 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: 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 the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC 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://www.nih.gov/grants/guide/notice-files/not98-030.html The title and number of the program announcement must be typed on line 2 of the face page of the application form, and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS 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 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 method? 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 The 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 in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priorities. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Thomas F. Kresina, Ph.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 6AN-12A Bethesda, MD 20892 Telephone: (301) 594-8871 FAX: (310) 480-8300 Email: tk13v@nih.gov Catherine McKeon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18B Bethesda, MD 20892-6600 Telephone: (301) 594-8810 FAX: (301) 480-3503 Email: Catherine_McKeon@nih.gov Direct inquiries regarding fiscal matters to: Ms. Donna A. Huggins Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 6AS-49K Bethesda, MD 20892 Telephone: (301) 594-8848 FAX: (301) 480-3504 Email: hugginsd@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 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. 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, and 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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