Full Text DK-96-010 CYSTIC FIBROSIS RESEARCH CENTER NIH GUIDE, Volume 25, Number 8, March 15, 1996 RFA: DK-96-010 P.T. 04 Keywords: Pulmonary Diseases Pathogenesis Treatment, Medical+ National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: October 8, 1996 Application Receipt Date: November 13, 1996 PURPOSE Cystic Fibrosis (CF) Research Centers will foster multi-disciplinary approaches to research ranging from elucidation of the molecular pathogenesis of CF to development of new therapies for this disorder. It is anticipated one award will be made related to this Request for Applications (RFA) in FY 1997. The receipt of one competing continuation application is anticipated, and this application will be in competition for the award together with other applications received in response to this RFA. 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, Cystic Fibrosis Research Center, is related to the priority area of chronic diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by 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 Support of this program will be through the NIH Specialized Center of Research (SCOR) (P50) award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement. 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. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. The anticipated award is for five years, contingent on the availability of funds. The maximum dollar request is limited to $750,000 in direct costs in any year. The anticipated award date is September 1, 1997. FUNDS AVAILABLE In FY 1997, it is anticipated that $727,000 in total costs will be committed to fund an application submitted in response to this RFA; however, this funding level is dependent upon the receipt of an application of high scientific merit. Applicants must limit their requests to not more than $750,000 direct costs in any budget period. 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. RESEARCH OBJECTIVES Improved therapy has transformed CF from a disease characterized by death in early childhood to a chronic illness with a median survival of nearly 30 years. However, there is still no cure for this devastating genetic disease affecting approximately 30,000 Americans. Since the cloning of the CF gene and identification of its protein product as a cAMP regulated chloride channel, molecular understanding of this disorder has progressed rapidly. Nonetheless many questions about molecular pathogenesis with important implications for therapy remain to be answered. The challenge now is to further define the molecular mechanisms underlying CF and to translate information about the molecular basis of disease into new treatments. Specialized Centers of Research (SCORs) are for the support of broadly-based multi disciplinary or multifaceted research programs that have well-defined major objectives or central themes. They are directed toward a range of scientific questions having a central research focus. They provide for integration of efforts of independent scientists investigating various aspects of the central theme. Each SCOR must have a clearly defined, unifying central theme to which each project relates and to which each investigator contributes. This theme must address the central questions relevant to elucidation of the pathogenesis of CF and/or development of new therapeutic approaches for CF. Collectively, these projects should demonstrate essential elements of unity and interdependence and result in a greater contribution to program goals than would occur if each project were pursued individually. These centers provide support for research projects, pilot and feasibility studies, as well as common resources and facilities (cores) which are available to the individual projects comprising the program. In order to be considered for funding, an application must have a minimum of three meritorious research projects. Cores must provide essential functions, services, techniques, determinations or instrumentation that will enhance at least two approved individual research projects. A multidisciplinary approach to a research objective, which constitutes the central feature of the SCOR, is key to maintaining the rapid expansion of our knowledge of CF. The dramatic progress in understanding the molecular basis of CF has been due in large part to collaborations among scientists with expertise in physiology, cell biology, molecular biology, structural biology, genetics, biochemistry, microbiology, and immunology. While the identification of the gene that is mutated in CF and of the function of the gene product as a chloride channel sparked a rapid series of advances in understanding the molecular pathophysiology of CF, many critical questions remain to be answered. Over 400 mutations have been identified and molecular mechanisms by which specific mutations cause dysfunction have been clarified, yet the relationship between genotype and phenotype remains obscure. Although 50 percent of CF patients in the general population are homozygous for the F508 mutation, the severity of disease varies among homozygotes, suggesting a role for other genetic or environmental factors. Ongoing work is elucidating the structure and functional domains of CFTR, probing the regulation of its channel activity, and defining the molecular and cellular basis by which mutations in CFTR cause clinical disease. This work provides the basis for rational design of pharmacologic approaches to enhance the opening of the defective CFTR chloride channel. The identification of abnormal sodium permeability in CF and elucidation of the relationship between CFTR and other epithelial ion channels suggest additional strategies for pharmacologic amelioration of this disorder. It is now recognized that many mutations, including F508, alter the processing of CFTR, producing a misfolded protein that is retained and degraded in the ER. Understanding of processing and trafficking of CFTR and how mutations alter the ability of the protein to attain the proper three-dimensional structure is vital to development of strategies to stabilize and improve trafficking of mutant CFTR. A critical question remains how a defect in CFTR generates the complex pathophysiology of the disease. CF affects multiple epithelial tissues resulting in characteristic lung disease, pancreatic insufficiency, biliary cirrhosis, meconium ileus, male infertility and elevated sweat chloride. Tissue specific expression of CFTR, the cellular and subcellular localization of wildtype and mutant CFTR within affected tissues, the role of CFTR in the development and function of specific cells and tissues, the pathways of electrolyte transport in affected epithelia, and the relationship between CFTR and other epithelial ion channels require further exploration. While the diverse pathology may be explained by defective chloride channel function, other mechanisms may also be involved. CFTR belongs to a family of transporters with multiple functions. CFTR has been linked to a variety of cellular processes, such as transport of molecules other than chloride, posttranslational processing of mucins and other proteins, endosomal acidification and other aspects of subcellular organelle function, exocytosis, and recycling of cell membranes. The potential impact of mutations in CFTR on these cellular processes must be explored. Delineation of the mechanisms underlying the inflammation and infection characteristic of CF and the predilection to pseudomonas infection will also elucidate the molecular mechanisms underlying the CF phenotype. Since demonstration that transfection of the CFTR gene corrects the chloride transport abnormality in affected epithelial cells, development of safe and effective methods of gene therapy has become a major goal of CF research. Development and optimization of gene transfer systems are rapidly evolving, and CF has been at the forefront of the application of this new technology to treat clinical disease. A variety of strategies employing viral-based vectors, liposomes and DNA conjugates are now being developed and tested. Toxic effects of vectors including immunologic responses are being evaluated, and potential strategies to ameliorate them are being identified. The cells that are appropriate targets for gene therapy in CF must be identified. Further work is needed to develop suitable vectors and promoters, to improve methods of gene delivery, leading to safe, stable and efficient gene transfer and expression in appropriate cells for gene therapy of CF. These are examples of research areas that would be considered responsive to this solicitation, and investigators may propose a variety of interrelated questions and approaches with the ultimate goal of enhancing our understanding of the pathogenesis of CF and ultimately curing this devastating disease. SPECIAL REQUIREMENTS A special interaction between the centers and the NIDDK is anticipated. To foster this interaction as well as cooperation among centers, the NIDDK may arrange periodic meetings of center investigators. Applicants should indicate a willingness to participate in such meetings and request travel funds allocated for participation in such meetings. 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 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 may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by October 8, 1996, 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 avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS 37-E - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES Because of the size and complexity of a SCOR, prospective applicants are urged to take advantage of the opportunity to consult with program staff listed under INQUIRIES early in the preparation of the application. Specific instructions for preparing a SCOR application should be requested. Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information Resources, Office of Extramural Programs, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: girg@drgpo.drg.nih.gov. The RFA label available in the PHS 398 (rev. 5/95) 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. Submit a signed, typewritten original of the application, including the Checklist, plus three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS 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 National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS 37-E, MSC 6600 Bethesda, MD 20892-6600 Applications must be received by November 13, 1996. If an application is received after that date, it will be returned to the applicant without review. 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. 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, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS 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 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 will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. Review Criteria o Significance of the research as related to the objectives of the RFA as set forth in the RESEARCH OBJECTIVES section above; o general 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 resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o 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; and 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 which 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 1, l997. The following will be considered in making funding decisions: o scientific merit as determined by peer review, o availability of funds, and o balance among research areas covered by the NIDDK CF Centers Program. 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: Judith Fradkin, M.D. Division of Diabetes, Endocrinology and Metabolism National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 5AN-12E 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8814 FAX: (301) 480-3503 Email: fradkinj@ep.niddk.nih.gov Direct inquiries regarding fiscal and administrative matters to: Donna Huggins Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8848 Email: hugginsd@ep.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 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, 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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