CYSTIC FIBROSIS RESEARCH CENTERS Release Date: May 10, 2001 RFA: RFA-DK-01-028 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) Letter of Intent Receipt Date: October 15, 2001 Application Receipt Date: November 13, 2001 PURPOSE Cystic Fibrosis (CF) Research Centers 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 that one award will be made in response to this Request for Applications (RFA) in FY 2002. The receipt of one competing continuation application is anticipated, and this application will be in competition together with other applications received in response to this RFA. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Cystic Fibrosis Research Centers, is related to the priority area of chronic diseases. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and nonprofit 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 RFA will use the National Institutes of Health (NIH) Specialized Center of Research (SCOR) grant (P50) award mechanism. Supplemental guidelines for preparing a SCOR application are available from Staff listed under Inquiries. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Applicants from institutions which 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 should be included with the application. This RFA is a one-time solicitation. The NIDDK only accepts new and competing continuation SCOR applications in response to an RFA. The total project period for an application submitted in response to this RFA may not exceed 5 years. The maximum dollar request is limited to $750,000 in direct costs for each budget period. The anticipated award date is September 1, 2002. FUNDS AVAILABLE The NIDDK intends to commit approximately $1,000,000 total costs in FY 2002 to fund 1 new or competing continuation grant in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $750,000 per year, excluding indirect costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Cystic Fibrosis is a genetic disease affecting approximately 30,000 persons in the U.S. This disease, which is present from birth, has had improved survival due to better management of the infections and nutritional aspects of the disorder. With the identification of the genetic cause of CF as mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), many studies have been undertaken to identify the functions of this protein and to determine the pathophysiology of the disease. It is clear that CFTR interacts with many other proteins including accessory proteins, scaffolding proteins and other ion channels to carry out its cellular function. Based on our current understanding of the functions and interactions of CFTR, new therapeutic interventions are being evaluated for both their efficacy and their safety. The interactions of researchers from many different backgrounds will be required to translate our understanding of the complex actions of CFTR into therapies for cystic fibrosis. Specialized Centers of Research (SCORs) support broadly-based multi- disciplinary or multifaceted research programs pursuing a range of scientific questions with a central research focus. 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) that 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. Each core 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 sparked a rapid series of advances in understanding the function of CFTR, the complex interactions of CFTR with other membrane proteins is beginning to be uncovered. In addition to its role as a chloride transporter, the important role of CTFR in regulating sodium and bicarbonate transport may be relevant to its pathophysiology. This central role of CFTR in regulation ion fluxes has made elucidating the pathophysiology of CF more difficult. Although 50 percent of CF patients in the general population are homozygous for the delta-F508 mutation, the severity of disease varies among homozygotes suggesting a role for genetic modifiers of the CF phenotype. One such modifier gene that determines meconium ileus has been localized to chromosome 19 in humans. Further work is needed to identify this gene as well as other potential genetic modifiers. In addition, classes of CFTR mutations are correlated with isolated symptoms of pancreatitis, chronic rhinosinusitis and congenital bilateral absence of the vas deferens. This enhanced ability to correlate phenotype and genotype will aid our ability to predict the severity of CF detected by genetic screening. Ongoing work has elucidated the structural and functional domains of CFTR and the regulation of its channel activity through its interactions with other proteins. The membrane protein, syntaxin 1A, has been shown to interact with the tail of CFTR preventing its interaction with the regulatory domain thus inhibiting channel activity. This interdomain regulation may provide a mechanism that could be exploited for pharmacologic approaches to enhance the opening of the CFTR chloride channel. In addition, CFTR binding to an accessory protein, CAP70, to form a CFTR dimer complex has been shown to enhance chloride channel activity. It is now recognized that many mutations, including delta-F508, alter the processing of CFTR, producing a misfolded protein that is retained and degraded in the endoplasmic reticulum. Understanding of processing and trafficking of CFTR and how mutations affect interactions of CFTR with other cell components involved in trafficking and/or 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. The mechanisms by which a defect in CFTR generates the complex pathophysiology of the disease require further definition. CF affects multiple epithelial tissues resulting in characteristic lung disease, pancreatic insufficiency, biliary cirrhosis, meconium ileus, male infertility and elevated sweat chloride. 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 and potential roles for CFTR have been identified in a variety of cellular processes. The potential impact of mutations in CFTR on these cellular processes must be explored. Since the demonstration that transfection of the CFTR gene to CF epithelial cells corrects the chloride transport abnormality, 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 for their ability to infect polarized cells. Potential strategies to ameliorate harmful effects of vectors, such as immunologic responses, are being evaluated. Further work is needed to develop improved methods of gene delivery, leading to safe, stable and efficient gene transfer and expression in appropriate cells for gene therapy of CF. Promising pharmacologic agents for the treatment of CF are under development. These pharmacologic approaches include: enhancing expression, folding and trafficking of mutant CFTR, increasing the activity of mutant CFTR, activating other membrane channels or cell processes to compensate for the defect in CFTR, and delivery of CFTR directly to affected cells. Development and testing of new therapies is key to delaying or preventing the life-limiting complications 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 finding new treatments for 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 are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by October 15, 2001, 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 plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms 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. All applicants should request a copy of Administrative Guidelines for Specialized Center of Research. These guidelines contain important additional suggestions and information on the format, content, and review of applications and review criteria. Prospective applicants may obtain guidelines from staff listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 4/98) 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, three 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) At time of submission, two additional copies of the application and all copies of appendix material must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. The Center for Scientific Review (CSR) 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 CSR 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 the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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, 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 the applications under review, 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 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 methods? 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 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 to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: October 15, 2001 Application Receipt Date: November 13, 2001 Peer Review Date: February March, 2002 Council Review: May 30-31, 2002 Earliest Anticipated Start Date: September 1, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review, o Availability of funds, o 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: Catherine McKeon, Ph.D. Diabetes, Endocrinology and Metabolic Diseases Division NIDDK 6707 Democracy Boulevard, Rm. 6103 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8810 FAX: (301) 480-3503 E-mail: Catherine.McKeon@nih.gov Direct inquiries regarding fiscal matters to: Florence Danshes Division of Extramural Activities NIDDK 6707 Democracy Boulevard, Rm. 734 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8861 FAX: 301-480-3504 E-mail: Danshesf@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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