Full Text DK-95-006 PATHOGENESIS AND TREATMENT OF CYSTIC FIBROSIS NIH GUIDE, Volume 24, Number 12, March 31, 1995 RFA: DK-95-006 P.T. 34 Keywords: Pulmonary Diseases Pathogenesis Biology, Cellular Biology, Molecular National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute Cystic Fibrosis Foundation Letter of Intent Receipt Date: October 24, 1995 Application Receipt Date: November 28, 1995 PURPOSE This Request for Applications (RFA) is intended to foster development of new therapies for cystic fibrosis (CF) through support of basic research on the pathogenesis of cystic fibrosis and its complications, application of advances in cell and molecular biology to understanding CF, translation of basic research into new treatments for CF, and clinical research on CF and its potential therapies. 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, Pathogenesis and Treatment of Cystic Fibrosis, 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: 202/783-3238). 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 Support of this program will be through the NIH research project grant (R01) award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The total requested project period for applications submitted in response to this RFA may not exceed four years. A maximum of three years can be requested for foreign awards. The maximum dollars that may be requested is limited to $160,000 in direct costs for the initial budget period with budget escalations in future years are limited to four percent over the initial budget period. The anticipated award date is July 1, 1996. Projects with substantial scientific merit that are not funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) or the National Heart, Lung, and Blood Institute (NHLBI) are eligible for support by the Cystic Fibrosis Foundation (CFF). Principal investigators will be responsible for forwarding copies of their summary statements and applications to the CFF for consideration for this award mechanism. The amount of CFF support will be determined by project scope and duration of funding will be limited to two years. No funds for indirect costs will be provided. FUNDS AVAILABLE For FY 1996, $2 million (total costs) will be committed by the NIDDK and $1 million will be committed by the NHLBI to fund applications submitted in response to this RFA. It is anticipated that approximately 15 awards will be made. An additional $2 million will be committed by the CFF to fund applications not funded by NIDDK or NHLBI. However, these funding levels are dependent upon the receipt of a sufficient number of applications of high scientific merit. Applicants must limit their requests to not more than $160,000 direct costs for the initial budget period and to four percent annual budget escalations in future years. Although this program is provided for in the financial plans of the NIDDK and the NHLBI, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background In the past three decades, improvements in clinical management of CF have increased the median survival from under five years to nearly thirty years. This improvement has largely resulted from improved management of infection, pulmonary secretions and nutrition. The identification, in 1989, of the gene that is mutated in CF sparked a rapid series of advances in understanding the molecular pathophysiology of CF. The function of the gene product, the Cystic Fibrosis Transmembrane Regulator (CFTR), as a chloride channel has been established and over 400 mutations have been identified. Ongoing work is elucidating the structure and functional domains of CFTR, probing the complex regulation of its activity as a channel, 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 of chloride channels in addition to CFTR suggests additional strategies for pharmacologic amelioration of this disorder. It is now recognized that many mutations, including the most common mutation causing CF, alter the processing of CFTR, producing a misfolded protein that is retained and degraded in the endoplasmic reticulum. Strategies to stabilize and improve trafficking of mutant CFTR could overcome this defect. Particularly exciting has been the finding that expression of normal CFTR can correct the chloride transport defect in affected CF epithelia. Development and optimization of gene transfer systems is rapidly evolving and CF has been at the forefront of the application of this new technology to the treatment and cure of clinical disease. Through the development of gene therapy and new pharmacologic approaches for treatment or cure of CF we may reap the full clinical benefits from the identification of the CF gene. This RFA is designed to address the molecular pathogenesis and the pathophysiology of CF and its complications, and to develop new approaches to therapy. Areas of research that would be responsive include, but are not limited to: Elucidation of the relationship between individual mutations and the clinical phenotype, and the molecular mechanisms by which mutations cause dysfunction; Identification of genetic or environmental factors that explain the variable clinical presentations and severity of disease associated with a given mutation; Studies of processing, trafficking and folding of CFTR, and the mechanisms by which specific mutations alter these events and the structure and cellular location of CFTR; Exploration of strategies to stabilize mutant CFTR and enhance its targeting to the cell membrane; Studies on regulation of CFTR activity, the mechanisms by which mutations alter CFTR function, and strategies for enhancing function of mutant CFTR; Elucidation of the pathways of electrolyte transport in affected epithelia, the relationship between CFTR and other epithelial ion channels, and the mechanism by which the rate of sodium transport is increased in CF; Identification and characterization of alternate chloride channels which might be activated to circumvent the chloride transport defect in CF; Exploration of potential roles of CFTR in 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, as well as exploration of the mechanisms by which mutations in CFTR may affect these processes; Studies of tissue specific expression of CFTR, and definition of the cellular and subcellular localization of wildtype and mutant CFTR within affected tissues, to elucidate the pathophysiology of CF and aid the development of strategies for gene and pharmacologic therapy; Development of safe and effective methods for gene therapy, including identification, characterization and optimization of suitable vectors and promoters, development of improved methods of gene delivery, identification of potential hazards of gene therapy, and testing gene therapy in vitro, in animal models and in human subjects. Delineation of the mechanisms underlying the inflammation and infection characteristic of CF and how mutations in the CF gene and alteration in CFTR function result in inflammation and infection; Studies of the pathophysiologic mechanisms underlying malnutrition and growth failure in CF, the relationship between pulmonary function, infection and nutritional status, and the extent to which achievement of normal nutrition and growth might ameliorate the rate of progression of lung disease and improve survival, and development and testing of strategies to improve nutritional status in CF; Studies of the pathophysiologic mechanisms underlying other complications of CF, such as increased risk of gastrointestinal malignancy, impaired fertility, liver disease, and diabetes, and development and testing of strategies to prevent or ameliorate these complications. These are examples of areas of research that are responsive to this solicitation and are not listed in order of priority. Investigators are free to propose additional areas of investigation responsive to the purpose of the RFA. 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 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 this RFA. 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 Natcher Building, Room 6AS-37F 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8886 FAX: (301) 480-3505 E-mail: hammondr@ep.niddk.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. The forms are available from most institutional offices of sponsored research; 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; and from the program administrator listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 9/91) 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 2a 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 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 Natcher Building, Room 6AS-37F 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Applications must be received by November 28, 1995. 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 Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NIDDK and the NHLBI. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIDDK and NHLBI staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Additional information will not be accepted after the official receipt date unless approved by the Scientific Review Administrator. 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 the review criteria stated below. As part of the initial merit review, a process (streamlining) 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 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 and methodology proposed 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 budget duration in relation to the proposed research; and 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. The initial review group will also examine the provisions for the protection of human and animal subjects, and for the safety of the research environment. Additional criterion for foreign applications: 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. AWARD CRITERIA The anticipated date of award is July 1, l996. The following factors will be used to make award decisions: scientific merit as determined by peer review, availability of funds, and programmatic priorities. 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 Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 5AN-12E 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8814 FAX: (301) 480-3503 E-mail: fradkinj@ep.niddk.nih.gov Susan Banks-Schlegel, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 2 Rockledge Center, Room 10018 6701 Rockledge Drive Bethesda, MD 20892 Telephone: (301) 435-0202 FAX: (301) 480-3557 Direct inquiries regarding fiscal and administrative matters to: Usha Ganti Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, 6AS-49B 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8868 FAX: (301) 480-3504 E-mail: gantiu@ep.niddk.nih.gov Tanya T. McCoy Division of Extramural Affairs National Heart, Lung, and Blood Institute 2 Rockledge Center, Room 7148 6701 Rockledge Drive Bethesda, MD 20892 Telephone: (301) 435-0171 FAX: (301) 480-3310 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, Diabetes, Endocrinology, and Metabolism and No. 93.838, Lung Diseases Research. Awards are made under the authority 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 routing 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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