Full Text DK-95-002 BASIC STUDIES OF RENAL CYSTIC DISEASE NIH GUIDE, Volume 23, Number 38, October 28, 1994 RFA: DK-95-002 P.T. 34 Keywords: 0715133 Biology, Cellular Biology, Molecular Genetics Biochemistry National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 28, 1995 Application Receipt Date: May 23, 1995 PURPOSE The Division of Kidney, Urologic and Hematologic Diseases (DKUHD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites investigator-initiated research project grant applications and Interactive Research Project Grants (IRPG), to encourage and facilitate studies designed to develop promising basic cellular, molecular, biochemical, physiological, and genetic approaches to autosomal dominant and recessive renal cystic diseases. 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 Request for Applications (RFA), Basic Studies of Renal Cystic Disease, is related to the priority area of chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and not for-profit organizations and institutions, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications may be submitted by single institutions and by a consortia of institutions. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from racial/ethnic minority individuals, women, and persons with disabilities are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grants (R01s), Interactive Research Project Grants (IRPG) and FIRST (R29) award support mechanisms. FIRST award applications must adhere to the R29 administrative guidelines (rev. 9/93) for eligibility, budget, and period of award. Responsibility for planning, direction, and execution of the proposed project will be solely that of the applicant. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also; however, requests must not exceed the NIDDK average grant size of $160,000 direct costs for the initial budget period for both R01s and IRPGs. The lead IRPG, however, may include a request for up to an additional $50,000 direct costs for shared resources (SPECIAL INSTRUCTIONS FOR PREPARING APPLICATIONS FOR INVESTIGATOR-INITIATED IRPGS should be requested from the Program Official listed under INQUIRIES). The total requested project period for R01 and IRPG applications submitted in response to the present RFA may not exceed five years. FIRST awards must be for five years and the total direct cost award for the five-year period may not exceed $350,000. The anticipated award date is September 30, 1995. This RFA is a one-time solicitation for fiscal year 1995. However, the NIDDK may reissue the RFA in future years. In anticipation that there will be a continuing program need, the NIDDK will encourage recipients of awards under this RFA to submit competing continuation applications that will be reviewed according to the customary peer review procedures. FUNDS AVAILABLE For FY 1995 $2.5 million in total costs per year, plus standard incremental increases for five years, will be committed by the NIDDK to fund applications submitted in response to this RFA. It is anticipated that 12 to 15 awards will be made. Although this program is provided for in the financial plans of the NIDDK, the award of grants, as well as the final amounts awarded, will be contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Adult autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease in the United States, affecting an estimated 1 in 500 to 1 in 1,000 people. Best estimates indicate that there are 600,000 ADPKD patients in the United States and that it accounts for 9 to 11 percent of all end-stage renal failure in this country; however, many ADPKD patients never reach end-stage renal failure and many reach end-stage only late in life. Studies indicate that progression of renal disease to end-stage in ADPKD is influenced by many factors in addition to the culprit gene, including: gender, race, age at diagnosis, hypertension, increased left ventricular mass, gross hematuria, mean renal volume, urinary tract infections (males), hepatic cysts (females) and three or more pregnancies (females). Currently, there is considerable interest in identifying intervention(s) that may slow down or arrest the progression of ADPKD. Among 200 ADPKD patients who participated in the recently reported Modification of Diet in Renal Disease Study, there was no substantial benefit of either a lower than usual blood pressure goal (e.g., <140/90 mmHg) or a low or very low protein diet on disease progression (rate of GFR decline) in patients with advanced disease. Supporting evidence indicates that renal cyst growth involves at least four primary pathogenetic mechanisms: 1. Abnormal Regulation of Epithelial Cell Growth, Resulting in Increases in Surface Area of Renal Tubules. Renal cysts are comprised of epithelial cells derived from progenitor renal tubules. These cells exhibit increased rates of proliferation, proto-oncogene expression and appear to be de-differentiated in respect to the tubule segment of origin. 2. Abnormal Transport by Epithelial Cells, Resulting in the Accumulation Within the Cyst Cavity of Fluid Derived from Glomerular Filtrate and Transepithelial Secretion. The fluid in renal cysts derives primarily from the transepithelial secretion of NaCl and water. This abnormality may be secondary to abnormal Cl- transport or Na+ secretion. 3. Remodeling of the Extracellular Matrix Surrounding Cysts. The extracellular matrix is abnormal in cystic kidneys. In the dominant form of the disease in humans, aneurysms, hernias, colon diverticuli, and floppy mitral valves suggest a connective tissue abnormality. 4. Gene Etiology of Hereditary Polycystic Kidney Disorders: Progress in Cloning. The cause of PKD is known in several disease states. The dominantly inherited disease, PKD1 has recently been shown to map to 16p13.3. The chromosome translocation associated with ADPKD that disrupts a gene (PBP) encoding a 14 kb transcript has been identified in the PKD1 candidate region. Further mutations of the PBP gene were found in PKD1 patients, two deletions (one a de novo event) and a splicing defect, confirming that PBP is the PKD1 gene. The recessive form, which affects primarily children, has not been defined. Medullary cystic disease has been recently assigned a 2P chromosomal location. The identification of the PKD1 gene is a major step toward understanding the molecular pathology of this complex disorder. Information currently available should allow study of the PKD1 protein to determine both its normal role in the cell and the mechanism by which mutation of the PKD1 gene cause the major renal cystic disease in humans. Progress in preventing and treating this disease will be enhanced when fundamental understandings of pathogenesis are achieved. The cross-fertilization of the disciplines of genetics and molecular biology, cell chemistry and biology, immunology, physiology, microbiology, and pathology have resulted in new and extremely useful experimental tools that allow researchers to address and seek answers to questions at a fundamental level. The regulation of cellular growth continues to be an area of intense investigation in kidney research and investigators have identified several growth factors and determined their exact chemical composition. The powerful tools of molecular biology (i.e., polymerase chain reaction and in situ hybridization techniques) offer further promise for expanding our knowledge about the regulatory genes that control differentiation and encode the signals that establish the precise topographical patterns essential to the function of the fully developed kidney. Fostering further research at the molecular level to address cellular and basic mechanisms, beginning with the developing kidney, may raise the possibility of new breakthroughs that will lead to effective treatment of ADPKD and/or its prevention. Research Goals and Scope This special grant program will support fundamental basic research, with an emphasis however, to foster extensive collaboration between individuals in the basic sciences, including biochemistry, cell biology, embryology, endocrinology, molecular biology, genetics, nutrition, pathology, pharmacology, renal physiology and in pathophysiology. It is the intent of this solicitation to engage investigators with diverse research interests who wish to apply their technologies and expertise in elucidating and extending the current understanding of the genetic aspects of autosomal dominant and recessive renal cystic diseases and the cellular and integrated mechanisms in the developing kidney. Some examples of renal cystic disease research directions in which applications would be considered responsive to this RFA include, but are not limited to: o Genes and gene products with critical roles in cystic kidney development and differentiation; o Expression of the protein(s) from the cDNA; o Studies of expression of ADPKD locus protein(s) during development and disease progression; o Definition of the mutations that cause polycystic kidney disease (autosomal dominant and recessive); o Mechanisms of action of growth factors and protooncogenes, cytokines, and other regulators of kidney growth and development in cystic kidneys; o Influence of extracellular matrix composition and architecture on kidney basement membrane in renal cystic disease; o Mechanisms underlying the involvement of specific ion, solute and water transporter(s) in ADPKD; development of inhibitors of solute and fluid secretion in ADPKD cysts; o Application of current knowledge of pathobiology of renal cystic disease to treatment in animal models; o Development of animals transgenic for renal cystic diseases (autosomal dominant and recessive), including the identification of modifier genes; o Development of cell lines for study of renal cystic disease. Investigators are not limited to the above examples of research areas, and are encouraged to propose other approaches that are appropriate to the investigator-initiated R01, Interactive Research Project Grant and FIRST (R29) mechanisms and the requirements of this RFA. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. For applications containing foreign collaboration components, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. 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 encouraged to submit an optional letter of intent by March 28, 1995. Included should be the descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and all 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 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: Robert D. Hammond, Ph.D. Division of Extramural Program Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 CENTER DR MSC 6600 Bethesda, MD 20892-6600 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/710-0267; and from the program administrator listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in the delayed processing of the application such that it may not reach the review committee in time for review. In order to assure proper identification of the application, line 2a of the application form must state "DK-95-002, Basic Studies of Renal Cystic Disease" and check the "YES" box. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must be sent to Dr. Hammond at the address listed under LETTER OF INTENT. Applications must be received by COB May 23, 1995 and no unsolicited material will be accepted after the official receipt date. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness by the NIDDK. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIDDK staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited grant applications during the next review cycle. As part of the initial merit review, a process (triage) may be used by an initial review group convened by the NIDDK in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications determined to be non- competitive will be withdrawn from further consideration and the Principal Investigator and the institutional official signing for the applicant organization will be notified. 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 July 1995 in accordance with review criteria stated below and Advisory Council review September 1995. The earliest requested begin-date should be September 30, 1995. Review Criteria o scientific, technical, or medical significance and originality of proposed research specific to the objectives of the RFA; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. AWARD CRITERIA Funding decisions will be based on the initial review group and national advisory council recommendations, program relevance, and availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Gladys H. Hirschman, M.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes, Digestive and Kidney Diseases 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7522 FAX: (301) 594-7501 EMAIL: GLADYSH@DVSGATE.NIDDK.NIH.GOV M. James Scherbenske, Ph.D Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes, Digestive and Kidney Diseases 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7522 FAX: (301) 594-7501 EMAIL: JIMS@DVSGATE.NIDDK.NIH.GOV For fiscal and administrative matters, contact: Mrs. Aretina Perry Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7543 Timetable Letter of Intent Receipt Date: March 28, 1995 Applications Receipt Date: May 23, 1995 Initial Review: July 1995 Council Review: September 1995 Earliest Start Date: September 30, 1995 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 Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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