INTERDISCIPLINARY CENTERS FOR POLYCYSTIC KIDNEY DISEASE RESEARCH Release Date: January 22, 1999 RFA: DK-99-012 P.T. National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 12, 1999 Application Receipt Date: April 13, 1999 PURPOSE It is the intent of this Request for Applications (RFA) to expand the basic research infrastructure in polycystic kidney disease (PKD), both for the autosomal dominant (ADPKD) and the recessive (ARPKD) forms. The development of Center grants has proven to be a valuable way to promote multidisciplinary interactions and to provide shared resources needed to address complex biomedical problems, such as therapy of PKD. Centers can provide the basis for generation of technologies which can be applied by other investigators and clinicians in many medical centers throughout the nation. Therefore, the purpose of the Interdisciplinary Centers for Polycystic Kidney Disease Research (ICPKD) is to attract a partnership of interdisciplinary research among investigators with scientific expertise who will use complementary and integrated approaches. The proposed studies should foster and extend the development of new approaches into the causes, early diagnoses, and improved treatments for PKD. Institutions with extensive scientific expertise in the areas of cellular and molecular biology, genetics, protein chemistry, structural biology, immunology, pathology, physiology, nutrition, epidemiology, clinical trials, and animal model and drug development are encouraged to apply. Eligibility for an award is limited to domestic institutions. 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 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, 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. Foreign institutions are not eligible for Center grants, however, with appropriate justification, collaborations with foreign investigators are allowed. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Any domestic institution or consortium wishing to qualify for an ICPKD should have an active program of excellence in basic and clinical biomedical research, not necessarily restricted to the kidney but to biological questions in general, which may have relevance to this initiative. Excellence of the proposal will be demonstrated by peer reviewed research support, publications in peer-reviewed journals, as well as substantive contributions to knowledge relevant to the research proposed within the Center application. Research projects to be supported by the ICPKD should be directed to the development of fundamental knowledge leading to understanding of the disease processes and the design of preventive and/or curative strategies. Core facilities should be shared resources that enhance productivity and aid in accomplishing the stated goals of the Center. Pilot and feasibility studies may also be included and independently supported by the ICPKD. Monetary resources for such new initiatives or feasibility studies may be for the support of new/young investigators, or established investigators who are moving into new areas of research directly related to the central goals of the Center. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Specialized Centers of Research (P50) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicants. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is a one-time solicitation and at this time the NIDDK has not determined whether this solicitation will be continued beyond the present solicitation; however, at the time the present initiative nears completion a follow up RFA will likely be issued in 2003. The anticipated award date for the successful applicants of the current RFA is September 1999. FUNDS AVAILABLE The NIDDK will commit $4.0 million in FY 1999 to fund up to four new Center grants in response to this RFA. An applicant may request a project period of up to five years and an adequately justified budget for direct costs of up to $750,000 per year, excluding indirect costs for consortium arrangements. Non- competing years will be limited to the NIH-wide escalation factor of 3 percent, but the total direct cost request cannot exceed the five-year direct cost cap of $3.75 million. 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. RESEARCH OBJECTIVES A. Background PKD is the fourth leading cause of end-stage renal disease (ESRD) in America, and contributes appreciably to the associated health care costs for renal failure in the ESRD population. A striking feature of PKD is the variability with which it affects the patient. Some develop only a modest number of renal cysts during their lifetime and may not be aware of being affected by this disorder. Others develop a massive number of renal cysts and may reach renal failure at an early age. It is not unusual for cysts to develop in the liver and within the systemic vasculature. Recent evidence indicates that besides the documented cyst enlargement and interstitial fibrosis, apoptotic loss of non-cystic nephrons is a significant component of the pathology of PKD and may contribute to the progressive loss of renal function. Despite the salient changes in the structural aspects of the kidney and the fact that ADPKD is one of the most common, potentially lethal genetic diseases known, little systematic research on the cellular mechanisms of the disease was carried out until the past two decades. Since then the growth of knowledge regarding this disease has been almost exponential. The identification and cloning of the PKD1 gene in 1995, followed by the discovery of its protein product, polycystin 1, and the sequencing of polycystin 2 in 1996, have led to further significant progress in studying this disease. The latter success can be attributed largely to the development of a PKD mouse model, which has allowed the study of the disease, especially in identifying the gene for the recessive form, ARPKD. Numerous mouse cystic kidney mutations have been described and further exploitation of these mutants and their genetic modifiers should continue to provide powerful resources to study genes and genetic interactions involved in PKD. B. Research Goals and Scope Although most recently the major focus of research on PKD has been to identify the genetic factors that cause the development of cysts and the progression of cyst-related changes within the kidney, the emphases of this initiative are more extensive. Therefore the following research goals are provided as potential areas of investigation that may be considered in developing innovative studies in an ICPKD. These are provided as examples and should not be viewed as restrictive or all inclusive: o Genetic Mechanisms: Define primary and secondary mutagenic mechanisms of PKD1 & PKD2; Localize and clone genes for other forms; Identify genetic loci or genes that modify the PKD disease process; Clone the ARPKD gene; Develop genomic reagents useful to these goals. o Biology of Polycystin function Define the structural topography of PKD1-2 proteins and their interacting partners; Define cellular and biochemical functions of PKD1-PKD2 and their downstream mediators; Identify genes responsible for renal cystic development and the progression of renal dysfunction in animal models. o Physiological Studies Develop physiological measurements in murine models of PKD; o Pathogenesis and Progression Define the basis for increased epithelial proliferation; Define the role of inflammation in disease progression; Define the role of the renal microvasculature in disease progression; Develop novel markers or end points to monitor the progression of renal dysfunction in PKD; Develop means to monitor renal dysfunction before the decline in GFR; Elucidate control of fluid secretion and accumulation in cysts. o Innovative therapeutic strategies for ameliorating the initiation of cyst formation and course of progression of renal dysfunction in humans and in animal models Explore treatments based on new pathogenic insights; Explore innovative therapies to ameliorate the course of disease using pharmacologic and gene therapeutic approaches in animal models; Explore innovative therapies to ameliorate the course of disease using pharmacologic therapeutic approaches in patients; Identify and initiate innovative treatments in specific cohorts of patients with unusual clinical characteristics (including extra-renal manifestations of disease) or rates of progression of renal disease. Description of a Center An ICPKD must be an identifiable organizational unit within a single university medical center or within a consortium of cooperating institutions with a university affiliation. The overall goal of an ICPKD is to bring together, in a cooperative, multidisciplinary and integrative manner, basic science and clinical investigators to enrich the effectiveness of research on PKD. To accomplish the overall goal of these Centers, there should be the existence at the applicant's institution an ongoing program of excellence in biomedical research related to the study of kidney disease. However, the research program need not be exclusively in kidney, and can include elements related to development, creation of animal models for use in fundamental studies, and the development of innovative, pioneering human investigation protocols. It would be highly desirable that the Principal Investigator, as well as the applicant institution, has a commitment to the fundamental investigation for treatment and prevention of kidney diseases. Close cooperation, communication, and collaboration among all participating center personnel of many professional disciplines are characteristics of a successful ICPKD. Research Projects The ICPKD grant consists of a cluster of individual, but interrelated, basic research projects, each with high scientific merit and clear research objectives. In the aggregate, the projects should be directed to the development of fundamental knowledge leading to understanding of the disease processes and the design of curative or preventive strategies. Criteria for designating an investigator as an ICPKD participant should be defined. Subsets of participants based on degree of participation or other measures are acceptable. Each ICPKD is encouraged to develop guidelines for ICPKD participation by investigators. Core Facilities Core facilities in an ICPKD are shared resources that enhance productivity or in other ways benefit a group of investigators working to accomplish the stated goals of the ICPKD. Cores should be designed to furnish a group of investigators with some technique, service, determination, or instrumentation in a manner that will enhance the research in progress, consolidate manpower effort, and contribute to cost-effectiveness by providing a service at lower cost and possibly higher quality than if each investigator were to attempt the same activity individually. Cores may be proposed in relation to any acceptable research activity of the ICPKD, but usually fall into one of four categories: (l) provision of a technology that lends itself to automation or preparation in large batches (e.g., radioimmunoassay and tissue culture); (2) complex instrumentation (e.g., electron microscopy or mass spectrometry); (3) animal preparation and care; and (4) technical assistance and training (e.g., molecular biology). Examples of possible core resources that would be considered within the scope of this request for applications include the following: o Molecular biology core to supply oligonucleotides and provide automated DNA sequencing capability; o Animal models core to develop, breed, and maintain animal models for diseases of PKD interest, which can be used to improve understanding of the human forms of the disease; o Tissue culture core for the harvest, cultivation, infection and handling of large numbers of cells; o Other cores needed to characterize gene transfer systems. These cores are not listed in any particular order, nor should they be construed to represent a comprehensive list of cores that could be fostered under this program. The establishment of and continued support for biomedical research cores within a ICPKD must be justified on the basis of use by Center investigators. The minimum requirement is significant usage by two or more principal investigators each with a Center project. A director must be named for each core. The organization and proposed mode of operation of each core should be described, with a plan for prioritizing investigator use of the core as well as the criteria for determining core users or potential users. Each core must have in place a procedure to evaluate efficiency and to maintain appropriate quality control. Limited developmental research is an additional appropriate function of a core facility, so long as the research is related directly to enhancing the function or utility of the core and is not an undertaking that should be funded through other mechanisms. Teaching the investigators and/or their staff members' new techniques and methodologies is also an important function of the cores. The cores are not intended to supplant investigator capabilities; rather, they are intended to enhance the opportunities of investigators to learn and become proficient in the technologies available through the core. Other types of activities also may be supported by an ICPKD, including optional pilot and feasibility (P&F) and enrichment programs. C. Pilot and Feasibility (P&F) Program The P&F program may provide modest support for innovative initiatives with the potential to advance progress in understanding cellular and molecular mechanisms of PKD. This program is directed toward both new/young and established investigators who wish to explore the feasibility of a novel approach to a problem in this area. Investigators eligible for P&F funding fall into three general categories: (1) new investigators without current or past NIH support as a principal investigator, and whose current or previous support from other sources have been modest; (2) established investigators with limited previous work in PKD who wish to apply their expertise to a problem in this area; and (3) established cellular and molecular genetics investigators who propose testing innovative ideas that represent a clear departure from their ongoing research directions. It is anticipated that the majority of the recipients of P&F funding will be from the first category. However, all eligible investigators must be independent investigators. Postdoctoral fellows or their equivalent are not eligible. Each pilot and feasibility study award is intended to provide a modest amount of support, not to exceed $50,000 direct costs, for a duration not to exceed two years, which will allow an investigator the opportunity to develop sufficient preliminary data to provide the basis for an application for independent research support. P&F study support is not intended for large projects by established investigators, which otherwise would be submitted as separate research grant applications. P&F funds also are not intended to support or supplement ongoing funded research of an investigator. Each P&F study proposal should state clearly the justification for eligibility of the investigator under one of the above three criteria. A proposed P&F study should present a testable hypothesis and clearly delineate the question being asked, detail the procedures to be followed, and discuss how the data will be analyzed. The P&F studies should be submitted for review generally in the format of NIH research project applications (R01), but with a 15-page limitation. The amount requested for individual pilot and feasibility studies in any given year cannot exceed 20% of the requested direct cost budget. Initial Review and Management of P&F Program Within this structure, each applicant institution must also establish a mechanism to oversee the use of funds for the proposed P&F program. This mechanism must include the use of appropriate consultants (described below) for review from the scientific community external to the ICPKD. These same consultants may, if desired, review and assess other activities of the ICPKD and may constitute the external advisory group to the ICPKD. The projects selected to receive these funds will be described by the Director in the annual progress report and will be given special attention by the NIDDK in its annual evaluation. D. Enrichment and Educational Program The ICPKD grant can budget for and provide limited support for an enrichment program, whose description and budget may be included within the administrative core. It may provide support for visiting scientists, seminars, and research forums. Limited travel support is allowable for ICPKD investigators to travel to present scientific findings, learn new laboratory techniques, develop new collaborations, or engage in scientific information exchange. In all cases, the enrichment program should further the overall aims and objectives of the ICPKD as well as of the scientific cores. Travel funds should be included for an annual meeting of the ICPKD directors. Center Administration An ICPKD will involve the interaction of broad and diverse elements within a single institution, or a consortium of cooperating institutions; thus the lines of authority and sanction by the appropriate institutional officials must be specified clearly. The administration of the ICPKD will include the responsibility of coordinating the various functions of the Center. Program Director Each applicant institution will specify a Center Director to be responsible for the organization and operation of the ICPKD. It would be highly desirable that the Center Director, as well as the applicant institution, has a commitment to the investigation of molecular and cellular topics relevant to kidney topics. The Center Director should be an experienced and respected individual who can provide scientific and administrative leadership for the total program. This individual must be able to coordinate, integrate, and provide guidance in establishing new programs in polycystic kidney disease research. An Associate Center Director should be named who will be involved in the administrative and scientific efforts of the ICPKD and will serve as acting director in the absence of the Center Director. B. Internal Executive Committee It is expected that the administrative organization of the Center will include a supportive structure, such as an internal executive committee to ensure accomplishment of (1) Coordinating and integrating the ICPKD components and activities; (2) Review the use of funds for pilot and feasibility studies; (3) Provide advice to the Director about the productivity and effectiveness of the activities of the ICPKD; and (4) Interact with the NIDDK and other appropriate individuals or groups including the scientific and lay communities, in order to help develop relevant goals. The final administrative structure of the ICPKD will, for the most part, be left to the discretion of the applicant institution (subject to review by the NIDDK). The NIDDK's experience has demonstrated that the effective development of an ICPKD program requires close interaction among the Center Director, the collaborating investigators, appropriate institutional administrative personnel, the staff of the awarding agency, and other members of the institution in which the ICPKD is located. Therefore, each ICPKD applicant should establish an administrative structure that will permit the development of such interaction. It is desirable for the Center administration to include an administrative assistant. C. External Advisory Committee The formation of an external advisory group to the ICPKD is encouraged. This group, comprised of 3-5 members, may advise the Center Director in the areas of budget, policy, collaborations, or other areas and may provide a scientific review group for the P&F program. While facilities (space, equipment, library, etc.) must be described in each element in the application, a more general description of the overall facilities and a statement regarding institutional commitment to the ICPKD also should be included in the description of the administrative organization. SPECIAL REQUIREMENTS Successful applicants, during the second year of the award and each year thereafter, may be expected to attend a yearly meeting of Renal Centers Directors convened by the NIDDK. Funds for this activity may be requested in the budget proposed for the respective center. 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 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 was 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: https://grants.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: https://grants.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. LETTER OF INTENT Prospective applicants are asked to submit, by March 12, 1999, 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.37F, MSC 6600 Bethesda, MD 20892-6600 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 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. 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. Submit a signed, typewritten original of the application, including the Checklist, and 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 the 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.37F, MSC 6600 Bethesda, MD 20892-6600 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Similarly, supplemental documents containing significant revision or additions will not be accepted after that date, unless the Scientific Review Administrator notifies applicants. 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 already reviewed, but such applications must include an introduction addressing the previous critique. Applicants are encouraged to contact the NIDDK staff as early as possible. Consultation between NIDDK staff and potential applicants prior to submission of the formal application is important. However, applicants should not construe advice given by the NIDDK staff as assurance of a favorable review. The NIDDK staff will not evaluate or discuss the merit of the scientific aspects of the application. Application Content and Format The instructions provided below modify and expand appropriate sections of Form PHS 398 to make it applicable for a Center request. These instructions are meant to be used with the PHS 398 instructions. It is important to follow the PHS 398 instructions closely. The "Illustrations" referred to below are suggestions for representing the information required in a format that has been proven useful in the submission and review of NIDDK program project applications. They can be obtained from the program official listed under INQUIRIES. Face Page, Page 1: Type "Interdisciplinary Centers for Polycystic Kidney Disease Research DK 99-012" on line 2. Complete all items on the face page as directed. Items 4 and 5 must have current approval dates. Description and Key Personnel. Page 2: List key professional personnel and describe the proposed research program, indicating the major thrust of the component projects. Do not exceed the space allowed. Table of Contents. Page 3 (Illustration 1): Identify each project, each core unit, the pilot and feasibility program (optional), the budget for each project, each core unit and the pilot and feasibility program, and supply the page number for each. Identify each project by title and assign each project a number that reflects the order of presentation. Assign each core a title and a letter designation. Use space under section 3 to list each project and core, their page numbers, and the individual project/core principal investigator. Number the following pages sequentially starting with the composite budget. List any appendix materials to accompany the application. Composite Budget: Center applications cannot request more than $750,000 annual total costs. A series of composite budgets are to be prepared: 1) A first-year budget for the Center using the page of Form PHS 398 entitled "Detailed Budget for First 12-Month Budget Period" (*Illustration 2). 2) The "Budget for Entire Proposed Project Period" using the appropriate budget page of Form PHS 398. The first year of support will reflect the category totals from "Illustration 2" budget. Omit budget justifications on this page, but include them with the individual project budgets. 3) A breakdown of the composite budget for each requested year as indicated in *Illustration 3. 4) Detailed budgets for each category for the first year only. In the "Personnel" category, list all professional and non-professional participants in the program, including those for whom no salary is requested, according to the format in Illustration 4. Similarly, present the detailed information for the remaining categories as specified in the instruction sheets for Form PHS 398. 5) The P&F program (optional) budget should be included within the Administrative Core. There should be a single budget for the P&F program as a whole rather than individual budgets for each P&F project. This total P&F program budget may not exceed 20% of the total direct costs annually. Biographical Sketch: Updated biographical sketches are required for all professional personnel. These should be prepared in accordance with the directions for Form PHS 398, arranged in alphabetical order, and placed in the application following the budget section. Current Sources of Support: Provide a detailed list of the sources of awarded and pending research support including fellowships and contracts for all participating investigators. All funding, including Federal, private, and institutional, must be identified. Follow the instructions of Form PHS 398, which require that each item provides: (a) the source of support, identifying number and title; (b) percentage of appointment on the project; (c) dates of entire project period; (d) annual direct costs; (e) a brief description of the Project; (f) whether the item overlaps, duplicates, or is being replaced or supplemented by the present application; delineate and justify the nature and extent of any scientific and/or budgetary overlaps or boundaries; and (g) any modifications that will be made should the present application be funded. In addition, summarize these data as shown in Illustration 6 of the appendix. Overall Research Plan: Using continuation pages, substitute the following for the Research Plan instructions of Form PHS 398: 1) Program Introduction and Statement of Objectives: Describe the rationale for the proposed research program. Explain the strategy for achieving the objective of the overall program, how each project and core unit relate to the strategy, and how the projects and cores relate to one another. It is important to document prior collaborative arrangements between investigators in the group, to emphasize the events that have led to the current application, to predict the anticipated unique advantages that would be gained by the research within the proposed Center, to describe how the projects are mutually reinforcing, and to explain how the projects collectively would achieve the stated objective of the proposed research. 2) Institutional Environment and Resources: Briefly describe the features of the institutional environment that are or would be relevant to the effective implementation of the proposed program. As appropriate, describe available resources, such as clinical and laboratory facilities, participating and affiliated units, patient populations, geographic distribution of space and personnel, and consultative resources. Organizational and Administration Structure of the Center: Describe in detail, and by diagram if appropriate, the chain of responsibility for decision-making and administration. Describe to whom the principal investigator/program director reports and the administrative structure as it relates to the individual project/core principal investigators. If advisory groups are included, indicate where in the chain of responsibility they fit and describe the specific functions of these consultants in the overall program. 3) Specific Managerial Responsibilities: Indicate who would be responsible for assisting the principal investigator/program director with the day-to-day administrative details, program coordination, and planning and evaluation of the program, and who would be in charge in the absence of the director. 4) Designation of Replacement for Principal Investigator: Describe procedures for appointing a replacement for the principal investigator if the need should arise. 5) Relation of the Center Organization and Administration to the Applicant Institution: Describe the relationships among the proposed Center and other existing research, academic, and administrative units of the applicant institution, such as centers, institutes, departments, and central administration. Indicate if any of the proposed cores will utilize or expand cores already existing at the institution, and the benefits that will derive from such an expansion. Research Projects: Use a separate Form PHS 398 for each project, and title and number each project sequentially so that it can be readily distinguished from other projects in the program. Each research project should be identified clearly by the same title as that provided in the Table of Contents. However, do not submit additional application face pages. Each project should begin with abstract and budget pages, which should be followed by information requested in Sections A through I of the instructions for Form PHS 398. Describe each in the same detail and format as required for a regular research grant application so that the scientific merit can be judged on the basis of the written application. For each project, adhere to the restrictions on number of pages and type size indicated in the instructions for Form PHS 398. The total number of pages for Sections A-D must not exceed 25 pages. Applications exceeding this page limitation will be returned to the applicant. As described under "Review Criteria," priority scores will be assigned to each individual research project as well as to the Center as a whole. Thus, the description of each project should be explicit enough to enable experts in related areas to understand the main thrust of each project without resorting to appendix materials to provide detailed procedures or critical data. The budget for each research project should adhere to the instructions from Form PHS 398. A detailed budget is required for the first year; budget estimates are required for all subsequent years of support. Explicit and detailed budget justifications must be included for all years. For example, all personnel positions, regardless of whether dollars are requested, must be clearly justified. All listed individuals must have a specified time commitment. Core Units: Use a separate Form PHS 398, and name and assign a letter designation to each unit. Provide a detailed budget for each core in the same way as for each project. Describe the core unit and the various services it would provide, as well as the personnel, facilities, management, and any special arrangements such as cooperation with other established cores. The core description should include a clear delineation of procedures, techniques, and quality control, and how core usage would be prioritized. If applicable, describe in detail statistical analyses and data management. Within each core, indicate which core services each project would utilize. In addition, prepare a table that indicates the research projects each core unit would serve and the proportion of the cost of the core unit associated with each research project (see Illustration 5 of the appendix). Pilot and Feasibility Program (optional): This program provides modest research support for a limited time (one to two years) to enable eligible investigators to explore the feasibility of a concept related to the mission of the Center and generate sufficient data to pursue it through other funding mechanisms. As described above, the P&F studies are intended to: (1) provide initial support for new investigators; (2) allow exploration of new leads or new directions for established investigators in kidney disease; and (3) stimulate investigators from other areas to lend their expertise to research in PKD. It is expected that the majority of the investigators will fall into the first category. All eligible investigators, however, must have faculty appointments and be independent investigators. Postdoctoral fellows or their equivalent are not eligible. Each P&F study proposal should state clearly the justification for eligibility of the investigator under one of the above three criteria. A proposed P&F study should present a testable hypothesis and clearly delineate the question being asked, detail the procedures to be followed, and discuss how the data will be analyzed. It must be on a topic related to the objectives of the Center. It should be submitted generally using the NIH research project application (R01) format, but the description of the proposed research should be limited to five pages. Projects should be focused, since funding for these studies is modest and is limited to two years or less. Any one investigator is eligible only once for this support, unless the additional proposed pilot and feasibility study constitutes a real departure from his/her ongoing research. The application should clearly describe and justify the pool from which potential pilot and feasibility applications will be selected. This can be limited to investigators at the parent institution or expanded to include investigators at institutions with a well-defined affiliation with the Center. Such an affiliation can occur either through a sub-contractual relationship for support of core resources or projects at a collaborating institution or through another mechanism supporting established collaboration between investigators of the Center with investigators at another institution. The mechanisms by which information on the availability of P&F awards will be disseminated and by which applicants will apply and be selected for these awards must be described and will be an important element in the review of the pilot and feasibility component of the Center. A P&F study award is intended to provide modest support which will allow an investigator the opportunity to develop sufficient preliminary data to provide the basis for an application for independent research support. P&F study support is not intended for large projects by established investigators which would otherwise be submitted as separate research grant applications. P&F funds are also not intended to support or supplement ongoing funded research of an investigator. Initial Review and Management of P&F Program By the very nature of this program, a significant responsibility for its management will be left to the Center administration during the project periods. During the review of the Center grant application, the P&F proposals are reviewed by the initial review group. These initial P&F studies must have been reviewed by the proposed Center management in the manner proposed for review of future studies, so that only those considered to be the highest quality are included in the grant application. The amount of P&F funds provided for the initial year will be based on the review of the approved studies. The budget for future years is recommended by the initial review group based on the quality of the P&F studies proposed, and the proposed method for management and review (as evidenced by this set of projects). Also considered will be the review group's evaluation of the future justification for continued P&F support. Since P&F studies can be awarded for any period of time up to two years, studies end at various times. In addition, the studies may also be terminated by the Center administration before their approved time limit for various reasons: for example, (1) the investigator may receive outside funding for the project; (2) the project was found not to be feasible; (3) the investigator may leave the Center institution; etc. When this occurs, the Center may make new awards for P&F studies with the remaining funds. While a Center's administrative framework for management of the P&F program is left up to each Center (subject to NIH peer review), certain minimal requirements must be met. The P&F program must have a director who is an established investigator in polycystic kidney disease. There must be a committee representing all the aspects of the Center, to assist the director in the management of the P&F program. Responsibilities of the director and the committee are to: (1) Maintain oversight and review of ongoing P&F studies; (2) Make recommendations regarding termination or other actions to the Center Executive Committee (or equivalent); (3) Prepare and ensure appropriate distribution of announcements of the availability of P&F funding; (4) Arrange and preside over the scientific merit review of proposals. At least one reviewer from outside the parent institution must be used for each proposal. All reviewers should assign priority scores in accordance with the NIH system. Copies of all of the proposals with written documentation of their reviews, priority scores, and final action must be retained by the Center. These records must be made available to reviewers if requested; (5) Maintain, insofar as is possible, a record of subsequent career events of each P&F study recipient; (6) Make recommendations to the Center Executive Committee (or equivalent) for final decisions. A record of actions by this committee must be documented and be made available if requested by the initial review group. The Center application should describe how these requirements would be met. There also should be an assessment of the relevance of proposed individual P&F studies and of the program as a whole, to research on PKD and to the specific goals and objectives of the individual Center and of the NIDDK Center program generally. Research Training Training postdoctoral fellows to conduct research in PKD is an associated activity of a Center. While stipends for fellows cannot be provided from Center grant funds, the establishment of a Center will invariably provide an enhanced environment for research training. Just as in the case of funding for individual research projects, funding for fellowships should be sought from NIH NRSA institutional training grants (T32, T35) and individual fellowships (F32, F33), and other sources such as private foundations, and commercial companies. Although no budgetary items can be included for research training, a section may be included in Center applications, which documents the potential for research training program in PKD, its relationship to the Center, and how the presence of the Center may enhance the program. Reporting Requirements and Annual Evaluation Annual progress reports, submitted as part of the annual non-competing continuation application, are used by the NIDDK and advisory committees to review the Center and its progress. These reports serve to verify in detail the achievement of the objectives outlined in the initial application and award. The NIDDK staff may, as necessary, assemble consultants to review the progress of the Center or to discuss major changes in the program that may require budget adjustments and/or review by the National Advisory Council. The progress report should describe the progress during the past budget year. This expanded progress report does not replace other management reports required by PHS policy. 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, a process will be used by the initial review group in which applications 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. Applications will not be reviewed by a site visit team, and therefore, the written application should be complete so as to facilitate review without a site visit. 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. Individual Projects 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 Appropriateness of the proposed budget and duration in relation to the proposed research 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. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. Cores The review criteria for scientific cores include: The appropriateness and utility of the core to the proposed center; each core unit must provide facilities or services to at least two research projects recommended for approval; The quality of the proposed facilities or services including administrative arrangements for utilizing the core; The qualifications, experience, and commitment of the personnel involved in the core; The appropriateness of the budget. Review and Management of the P&F Program During the review of an ICPKD grant application, the P&F proposals are reviewed by the initial review group in a manner similar to a study section review. Because P&F studies may be awarded for a time period of up to 2 years, studies may end at various times. In addition, the studies also may be terminated by the ICPKD Director before their approved time limit for various reasons. When such situations result in the termination of the study, the ICPKD may make new awards for P&F studies with the remaining funds. The administrative framework for management of the ICPKD's P&F program is left to the ICPKD's discretion, so long as certain minimal requirements are met. Each ICPKD Director is encouraged strongly to involve the external advisory group in the management of the program. The management of the program must include provision for (1) oversight and review of ongoing P&F studies; (2) termination of projects or other appropriate actions; (3) preparation and appropriate distribution of announcements of the availability of P&F funding; (4) scientific merit review of P&F proposals; (5) maintenance of a record of subsequent results (abstracts, publications, R01 submissions, etc.) of each P&F study recipient; and (6) a mechanism for making recommendations to the ICPKD Director for funding decisions. A record of actions must be documented and must be made available to the reviewers if requested. Overall Center Program The review criteria for the overall Center program include: The scientific merit of the program as a whole; The significance of the overall goals of the Center; The cohesiveness and multi-disciplinary scope of the Center and the coordination and interrelationship of the projects and cores to the common theme of the Center; The leadership, scientific expertise, and commitment of the proposed Center Director. Center Administrative Considerations For all Center applications, the review will assess: The institutional environment for and resources available to Center investigators; The institutional commitment to the proposed Center; The administrative leadership necessary to provide for the quality control of supported projects in the Center, the allocation of funds and the ability to foster communication and cooperation among Center investigators. Schedule Letter of Intent Receipt Date: March 12, 1999 Application Receipt Date: April 13, 1999 Peer Review Date: June - August, 1999 Council Review: September 8-9, 1999 Earliest Anticipated Start Date: September 30, 1999 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 is welcomed. Inquires regarding programmatic issues may be directed to: M. James Scherbenske, Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS.19E, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-7719 FAX: (301) 480-3510 Email: scherbensk@extra.niddk.nih.gov Inquiries regarding fiscal matters may be directed to: Mrs. Helen Y.S. Ling Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 6AN.44F, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8857 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849. 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 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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