INNOVATIVE RESEARCH APPROACHES TO BASIC BLADDER BIOLOGY AND THE PAINFUL BLADDER SYNDROME Release Date: January 22, 1999 RFA: DK-99-014 P.T. National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 14,1999 Application Receipt Date: April 12, 1999 THIS RFA USES THE MODULAR GRANT CONCEPT. THIS RFA INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites investigators to apply for research grants on basic bladder biology and painful bladder syndrome, including Interstitial Cystitis (IC). The painful bladder syndromes are common chronic disorders with persistent and disabling symptoms that include urinary frequency, urgency and bladder and pelvic pain. This solicitation invites applications for basic research studies on the molecular and cellular biology of the bladder urothelium, mechanisms of pain perception in the bladder, and the relationship between neuromuscular innervation and bladder function. Pilot and feasibility studies in human subjects focusing on innovative treatments for interstitial cystitis and other syndromes of bladder and pelvic pain and new markers of disease are also a focus of this initiative. The overall goal is to enhance the understanding of the molecular, genetic, and cellular pathophysiology of the normal urinary bladder and the bladder in painful bladder syndromes and to develop new and innovative clinical approaches to these disorders. The intent of this Request for Applications (RFA) is to intensify investigator-initiated research, attract new investigators to the field, and increase interdisciplinary research to broaden the scope and effectiveness of research in this area. 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, Innovative Research Approaches to Basic Bladder Biology and the Painful Bladder Syndromes, is related to the priority area of chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000 at ELIGIBILITY REQUIREMENTS Research grant applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, laboratories, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. Competitive renewal applications (Type 2) and revised applications are not acceptable for this request. MECHANISM OF SUPPORT This program will be supported through National Institutes of Health (NIH) Research project Grants (R01), Interactive Research Project Grants (IRPG), and Exploratory Research Grants (R21). Investigators without prior R29 or R01 support are encouraged to apply for this RFA and to identify their status as new investigators on the front of the grant application. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement. Applications from Institutions with a General Clinical Research Center (GCRC) funded by NIH's National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications and revised resubmission of applications from this solicitation will compete with investigator-initiated applications and be reviewed according to customary procedures. R01 applications submitted in response to this RFA may not request a total project period of more than 5 years. A maximum of 3 years can be requested for foreign awards. In general, the maximum budget request for R01 applications should be limited for $160,000 in direct costs for the first budget year. Requests for support that exceeds that amount will require a thorough justification, and in no case will a request exceeding $250,00 in direct costs for the first budget year be allowed under this solicitation. R21 (Exploratory Research Grant) applications may not exceed 3 years for the total project period. The maximum budget request for R21 applications may not exceed $75,000 in direct costs for each of the three budget periods. The R21 grant mechanism may be used by new investigators and experienced investigators to develop pilot and feasibility studies for new and innovative approaches to clinical aspects of IC, especially exploration of therapeutic interventions and biomarkers of disease. R21 applications generally are expected to have little preliminary data and are reviewed based on the development of hypotheses and supporting literature. All applications must budget for travel to an annual meeting at the NIH or in the Washington, D.C. area. The anticipated award date for all grants is September 30, 1999. FUNDS AVAILABLE A total of $2.0 million in total costs will be committed by the NIDDK in fiscal year 1999 to fund applications of high scientific merit submitted under this RFA. This funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. It is anticipated that 10 to 12 awards will be made, depending on the mix of R01 and R21 grants awarded. Although this program is provided for in NIDDK's financial plan, the award of grants under this RFA is also contingent on the availability of funds for this purpose. RESEARCH OBJECTIVES Background The painful bladder syndromes are a group of disorders manifest predominantly by pelvic pain and bladder instability, usually urinary urgency and frequency. IC is a major disorder in this group of syndromes. There is no scientifically demonstrated etiology for these disorders, and the pathological and pathophysiological features of bladder tissue from patients are variable and have not been well correlated with symptoms. Although the scientific literature on IC is increasing, many theories about pathological changes in the bladder still have not been rigorously tested. One impediment to understanding IC is the lack of basic knowledge about the pathology of the urinary bladder. Painful bladder syndromes are primarily described clinically and can be roughly divided into three categories based on the clinical course: 1) people whose symptoms subside spontaneously with relatively infrequent, self-limited flares; 2) people with chronic symptoms but steady objective findings: 3) people with chronic symptoms and a progressive disorder that results in an "end-stage" physically and functionally smaller bladder. Both stress and urge urinary incontinence may be present to varying degrees, especially in people in groups 2 and 3. These three categories may represent separate diseases or different manifestations of the same underlying problem. The development of reliable serum or urine markers of inciting pathology and/or correlates of disease severity, pathology, and prognosis would represent significant progress in understanding and treating painful bladder syndromes. Well-designed clinical studies of painful bladder syndromes may also provide information on which to base studies of etiology and pathobiology. Scientific Objectives The following examples of research topics are just a few that could be considered for support under this RFA. We anticipate that many applications ultimately funded under this RFA may, in fact, propose topics that are not listed: o To increase the molecular, cellular, and genetic understanding of the relationship between the bladder epithelium, it's underlying tissues, its innervation, and the pelvic floor. o To develop methods to identify and separate bladder cells from the urine, utilizing fluorescent activated cell sorting. o To develop biomarkers of disease in women with painful bladder syndromes and correlate markers with symptoms and prognosis. o To define the relationship between pathological findings in human tissue and mechanisms of disease pathogenesis. o To test innovative hypotheses about the etiology and pathogenesis of painful bladder syndromes. o To characterize the molecular and cellular effects of therapeutic agents on bladder tissue and correlate with symptoms. Program Objectives: o To increase the diversity of scientific expertise applied to basic research studies of the urinary bladder and the pelvic floor. o To increase the diversity of expertise in clinical and allied disciplines applied to painful bladder syndromes. o To verify the existing knowledge about the pathology and pathogenesis of painful bladder syndromes by developing and conducting rigorous clinical and basic science studies utilizing human subjects and tissues. o To develop innovative genetic and bioengineering approaches to studies on the bladder and the painful bladder syndromes. Research Scope: Clinical research is defined as studies involving people with painful bladder syndrome and, if necessary, appropriate control subjects. Basic research studies may involve tissue from human subjects, either with disease or controls, or animal models or tissues. Clinical research on biomarkers of disease and clinical interventions are limited to people with documented IC or chronic pelvic pain and to normal control subjects. Animal models are not valid for these studies. SPECIAL REQUIREMENTS Clinical research studies on IC must use the NIDDK Research Criteria for IC for inclusion of patients. The scope of clinical patients may exceed the NIDDK criteria, but rationale and diagnostic criteria must be well defined and justified. All animal models used for basic research studies must delineate the limitations of the model. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in al 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 subjects of the purpose of the research. This new 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 "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: INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the 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: Investigators also may obtain copies of the policy 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 14, 1999, a letter of intent that includes a descriptive title of the proposed research; the name, address, and the 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 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) 549-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used to apply for grants under this RFA. These forms are available at most institutional offices of sponsored research and 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: Special Instruction For R01 Submissions Modular Grants All R01 grants will be awarded as modular grants. The modular grant concept established specific modules (increments) in which direct costs may be requested and a maximum level for requested direct costs. Only limited budgetary information is required in the application; a detailed budget need not be provided. Sample budgets and justification pages will be provided upon request from Ms. Trude Hilliard at the address listed under INQUIRIES or following submission of a letter of intent. Budget Instructions The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o Face Page: As a reminder, Item 7 should be completed to indicate Modular Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus F&A costs). O Detailed Budget For The Initial Budget Period: Do not complete Form Page 4 of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. O Budget For The Entire Period Of Support: Do not complete the categorical budget on Form page 5 of the PHS 398 (rev. 4/98). Only the requested total direct costs line for each year must be completed based on the number of $25,000, modules being requested. Applicants may not request a change in the amount of each module. A maximum of TEN MODULES ($250,000 direct costs) per year may be requested and each applicant may request up to FIVE years of support for R01 applications, as specified in the MECHANISM OF SUPPORT section of this RFA. Direct cost budgets of modules requested will remain constant throughout the life of the project ( i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules to be requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs of the Entire Proposed Project Period should be shown in the box provided. O Budget Justification: Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398 - List the names, role on the project and proposed percent effort for all project personnel (salaried and unsalaried) and provide a narrative justification for each person based on his/her role on the project. UNDER THE JUSTIFICATION FOR THE PRINCIPAL INVESTIGATOR, INDICATE IF YOU ARE A NEW INVESTIGATOR (i.e., AN INVESTIGATOR WITHOUT PRIOR R29 OR R01 SUPPORT). - Identify all consultants by name and organizational affiliation and describe the services to be performed - Provide a general justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-item purchases, such as large equipment requests, must be accommodated within these limits. No specific costs for items or categories should be shown. o Consortium/Contractual Costs: If collaborations or subcontracts are involved that require transfer from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and indirect) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall $175,000 direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract funds are added to the parent grant budget, the total direct cost amount must be indicated in the number of $25,000 modules requested. o Biographical Sketch: A biographical sketch is required for all key personnel, following the modified instruction below. Do not exceed the two-page limit for each person. - Complete the education block at the top of the form page - List current position(s) and those previous positions directly relevant to the application; - List selected peer-reviewed publications directly relevant to the proposed project, with full citation; - The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. O Other Support: Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other support information will be requested by Institute Staff if there is a possibility for an award. o Checklist: No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by Institute Staff if there is a possibility for an award. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. R01 applications not conforming to these guidelines will be considered unresponsive to the RFA and will be returned without further review. THE MODULAR GRANT APPLICATION DOES NOT APPLY TO R21 GRANT APPLICATIONS (follow instructions the PHS Form 398 rev. 4/98). 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, plus 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 April 12, 1999. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application is 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. REVIEW CONSIDERATIONS Applications will be reviewed for completeness by the CSR and responsiveness by NIDDK. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit 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 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. o Significance: Does this study address an important problem? If the aims of the applications 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? o 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? o 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? o 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)? o 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? o Reasonableness of the proposed research 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 as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects when necessary will also be evaluated. o 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. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA The following will be considered in making the funding decisions: o Quality of the proposed project as determined by peer review o Uniqueness of proposed studies o Availability of funds o Program priorities INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any questions from potential applicants is welcome. Inquiries regarding programmatic issues should be directed to: Leroy M. Nyberg, Jr., Ph.D., M.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center drive, Room 6AS-13, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: Inquiries regarding fiscal, budget and administrative matters, including the modular grant preparation, should be directed to: Trude Hilliard Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center drive, Room 6AN-38, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8859 FAX: (301) 480-3504 Email: Schedule Letter of Intent Receipt Date: March 14, 1999 Application Receipt Date: April 12, 1999 Initial Review: June-July 1999 Advisory Council Review: September 1999 Anticipated Date of Award: September 30, 1999 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 Regulation 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health System Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of tobacco products. In addition, Public Law 103-277, 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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