BASIC RESEARCH IN INTERSTITIAL CYSTITIS RELEASE DATE: November 25, 2002 RFA: DK-03-010 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( LETTER OF INTENT RECEIPT DATE: January 21, 2003 APPLICATION RECEIPT DATE: February 21, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA In the present Request for Applications (RFA), the Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites applications for basic cellular, molecular, and genetic research and translational studies focused on understanding the causes and pathogenesis of interstitial cystitis (IC). One aim of this RFA is to attract new and established investigators from related research areas to apply their knowledge to the study of IC. Such related areas include: inflammation, epithelial biology, cellular biology, molecular genetics, neuropathology and neurophysiology, the biology and physiology of pain, diagnostic radiology and nuclear medicine, genomics, proteomics, the development of genetic animal models, autoimmunity, etc.. The development of productive research collaborations between investigators with diverse scientific backgrounds is another highly relevant aim of the RFA. This RFA is a part of NIDDK's commitment to encouraging and supporting new and innovative high-quality basic and translational studies that will provide insights into this chronic, painful and disabling disorder. RESEARCH OBJECTIVES A. Background Interstitial cystitis (IC) is a debilitating, chronic bladder syndrome consisting of urinary urgency, frequency, and pain in the bladder and surrounding pelvic region. It has been estimated that IC may affect as many as 1 million American men, women and children of all ages and races; however, approximately 90% of the reported sufferers are women. Diagnosis of IC is primarily based on symptoms, as there are no currently available blood or urine tests due to the lack of demonstrated biological markers. The NIH has established IC diagnostic criteria (ref: Journal of Urology 140: 203-206, 1988) for use in research studies. There are currently no consistently effective treatments for IC, which remains an idiopathic heterogeneous disorder of unknown causes. A precise etiology for IC has not been demonstrated. Although there are a number of theories about the pathology of IC, none has been scientifically tested and proven. These theories include the possibility of defects in the protective lining of the bladder, an immunogenic or autoimmune disorder, or defects in innervation of the bladder. The possibility that heredity may contribute to susceptibility to IC is another emerging area of interest. This RFA funding initiative will provide support for basic cellular, molecular, and genetic research and translational studies pertinent to IC from both new and established investigators in relevant fields of investigation. Topics of special interest include, but are not restricted to, the etiology and pathogenesis of IC; innovative diagnostic imaging studies; identification of disease markers and the molecular biology of IC; neurophysiology and bladder innervation and pain pathways; and the genetics of IC susceptibility, causality, and disease progression. The development of animal models for the study of IC has been an area of special interest, but concern exists that animal models in which bladder pathology is induced through the local administration of irritants may not provide a valid model of human disease. The identification and characterization of new animal models with a genetic predisposition to IC-like syndromes or those generated through transgenic technologies are considered to be of special interest, however. The goal of the NIDDK in developing this RFA is to support basic and translational studies that will aid in the future development of reliable IC predictive and diagnostic tools, such as blood and urine tests/screen, and new and effective disease treatments and prevention strategies. Achieving the goals outlined in the RFA initiative is deemed a high-priority by the Bladder Research Progress Group (BRPRG) B. Objectives and Scope The present RFA is intended to encourage and support basic cellular, molecular, and genetic research and translational studies relevant to IC. Through this initiative the NIDDK hopes to expand current areas of IC research and extend IC research into new or understudied areas of investigation. The NIDDK also seeks to attract investigators already established in relevant related research areas. Remarkable advances have recently been made in the understanding of the molecular and genetic basis of disease. Translational research is the process of applying these ideas, insights, and discoveries to the treatment or prevention of human disease by utilizing the combined research efforts of basic, applied and clinical scientists. Research areas of special interest and anticipated outcomes/goals include, but are not limited to, the following: o The etiology and pathogenesis of IC. Especially critical areas of basic IC research are the identification of initial causal factors and factors that influence the course of the disease. Examples of relevant topics include bladder permeability and immunologic and neurogenic factors as related to IC cause and progression. Studies in these areas, as well as new and novel areas of IC cause/pathology, are highly encouraged. Such work might include collaborative research on the cause and pathogenesis of IC and potentially related disorders such as chronic prostatitis, chronic pelvic pain syndrome, irritable bowel syndrome, Crohn's disease, vulvodynia, etc. o Disease markers and molecular biology of IC. The identification of molecular markers for IC is a critical area of basic research. The identification of disease markers from tissues such as blood and urine is encouraged, though studies of markers from more invasive biopsy samples are also appropriate. Identification of markers may involve a variety of molecular methodologies such as microarray and mass-spectroscopy assessment of gene expression and identification of protein type and levels. Markers that can be used in sensitive, specific tests/screens for IC may prove of immense value in the accurate diagnosis, and even early prediction, of disease. Studies that further describe already reported markers, as well as identify new markers are encouraged. o The neurological aspects of IC. Studies that investigate the neural properties of relevant cell-types, such as bladder urothelium, and how these properties are altered in IC are encouraged. Studies of bladder afferent neurons are also deemed highly significant. Strongly encouraged areas of study also include the analyses of relevant neurologic cells/tissues and bladder innervation through molecular and imaging strategies, neurophysiology and neuropathology studies, and studies of factors influencing pelvic pain pathways. Investigations in these important areas should provide insight into many particularly debilitating IC symptoms such as urgency, pain associated with bladder filling and urination, and generalized pelvic pain. o The genetics of IC susceptibility, causality and disease progression. Evidence exists suggesting a possible genetic basis for IC susceptibility. Studies utilizing existing cohorts of twins would be especially encouraged. o The application of established and innovative diagnostic and imaging techniques to the study of IC. For example, the development and utilization of radiological and nuclear medicine techniques to visualize and diagnose the urinary bladder affected with IC. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health R01 (Research Project) and R21 (Exploratory/Development Project) award mechanisms (for a description of R01 and R21 awards see This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is December 2003. The R01 award represents an investigator-initiated research grant designed to support a discrete, specified research project performed by a principal investigator. It is envisioned that R01 grants awarded through this RFA will provide up to $250,000 per year in direct costs for a maximum period of five years. The R21 award is intended to encourage exploratory research projects where sound methodology and strong rationales exist, but for which preliminary data do not. R21 grants awarded through this RFA will provide up to $100,000 per year in direct costs for a maximum of two years and may not be renewed. The R01 mechanism should be used in cases where the applicant has developed a body of preliminary data or previous methods or technology upon which the application will build. An annual meeting of all investigators funded through this RFA will be held in the Bethesda, MD. Each applicant (foreign and domestic) must include in their budget sufficient funds to cover travel costs to that annual meeting. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Applications that exceed $250,000 in direct costs per year must follow the instructions for non-modular research grant applications. FUNDS AVAILABLE The NIDDK intends to commit approximately $5,000,000 in FY 2003 to fund approximately 20 to 25 new grants in response to this RFA. A R01 applicant may request a project period of up to five years and a budget for direct costs of up to $250,000 per year. A R21 applicant may request a project period of up to two years and a budget fore direct cost of up to $100,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIDDK provide for support of this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued in the future. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS ANNUAL MEETING OF INVESTIGATORS: An annual meeting of all principal investigators funded through this RFA will be arranged by the NIDDK and held in the Bethesda area. The purpose of this meeting is for investigators to report on progress of their studies, to develop collaborative research relationships, and to establish a network of investigators who will exchange new, innovative ideas for research. It is envisioned that this annual meeting will be held in conjunction with other NIDDK funded projects. Each applicant (foreign or domestic) must include in their budget adequate funds to cover their travel and hotel expenses for this two-day meeting. DATA SHARING: Data sharing achieves many important goals for the scientific community, such as reinforcing open scientific inquiry, encouraging diversity of analysis and opinion, promoting new research, testing of new or alternative hypotheses and methods of analysis, supporting studies on data collection methods and measurement, facilitating teaching of new researchers, enabling the exploration of topics not envisioned by the initial investigators, and permitting the creation of new data sets by combing data from multiple sources. Application submitted in response to this RFA must include a data-sharing plan in the application. This will also be included in the review of the application. Information regarding data sharing may be found at: WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Chris Mullins, Ph.D. Director of Basic Cell Biology Programs Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes, Digestive and Kidney Diseases 6707 Democracy Blvd., Room 637 Bethesda, MD. 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: Leroy M. Nyberg, Jr., Ph.D., M.D. Director, Urology Programs Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes, Digestive and Kidney Diseases 6707 Democracy Blvd., Room 637 Bethesda, MD. 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: o Direct your questions about financial or grants management matters to: Ms. Helen Ling Senior Grants Management Specialist Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 732 Bethesda, MD 20892-5456 Telephone: (301) 594-8857 FAX: (301) 480-3504 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chris Mullins, Ph.D. Director of Basic Cell Biology Programs Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes, Digestive and Kidney Diseases 6707 Democracy Blvd., Room 637 Bethesda, MD. 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SUPPLEMENTAL INSTRUCTIONS: SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS: All application instructions outlined in the PHS 398 application kit are to be followed, with the following requirements for R21 applications: 1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $100,000 per year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15 page limit of items a-d of the research plan SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 RFA label is also available at: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and five 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 (for express/courier service: Bethesda, MD 20817) APPLICATION PROCESSING: Applications must be received at the CSR 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. 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. PEER REVIEW PROCESS 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 NIH in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the National Diabetes, 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem related to interstitial Cystitis? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o DEVELOPMENT OF ANIMAL MODELS: The identification and characterization of animals with a genetic predisposition to IC-like syndromes or those generated through transgenic technologies are considered highly preferable to analyses of animals in which pathologies are induced through the administration of agents. o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data o DATA SAFETY MONITORING PLAN: If relevant, the adequacy of the data safety monitoring plan. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o OTHER CRITERIA: (For investigators previously funded by the NIDDK for IC related research). How does this proposed project build on your previous NIDDK supported work on IC? RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 21, 2003 Application Receipt Date: February 21, 2003 Peer Review Date: June/July 2003 Council Review: September 24-25, 2003 Earliest Anticipated Start Date: September 2003 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. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.849 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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