Full Text PA-96-029 RENAL FILTRATION BARRIER AND ITS CELLULAR COMPONENTS NIH GUIDE, Volume 25, Number 4, February 16, 1996 PA NUMBER: PA-96-029 P.T. 34 Keywords: 0715133 Biology, Cellular National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), through its Division of Kidney, Urologic and Hematologic Diseases is the principal agency that supports fundamental and applied research directed at normal renal structure, function and regulation. This includes studies utilizing whole kidney and/or the selected segments of the kidney or individual cells or any of their subcellular components as models. The purpose of this program announcement is to stimulate research on the glomerular portion of the nephron, with special emphasis on the glomerular capillary wall and its cellular constituents, namely, the glomerular endothelial and epithelia (podocytes) and the glomerular basement membrane (GBM). Although a third cell type, the mesangial cell, is usually not considered a member of the glomerular wall proper, it may influence the functions and dimensions of the wall and transiently migrate onto or into the wall. Also, glomerular capillary morphogenesis is highly complex, involving mediators that are present in the developing kidney and within renal epithelial cells undergoing differentiation, which need to be explored to provide new insights into the fundamental mechanisms that result in the formation of glomerular capillaries in vivo. Numerous observational and experimental studies have shown that disruptions in glomerular cell shape and adherence and/or GBM composition result in loss of valuable plasma constituents to urine. Virtually every example of proteinuria in humans can be traced to morphologic abnormalities in the glomerular wall. The interactive play among receptors, modulatory proteins, phospholipid metabolites and second messengers is now becoming clearer in the modulation of cytoskeletal organization, and growth and differentiation of the kidney. There are now cellular and molecular biologic techniques that make it possible to identify and clone genes and proteins to further expand research activity on the glomerulus. 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. Potential applicants may obtain a copy of "Healthy People 2000 (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign 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 First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) individual research project grant (R01) and FIRST (R29) award mechanisms. 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 proposal in response to this PA may vary, it is anticipated that the size of an award will vary also; however, the support of requests exceeding the NIDDK average grant size of $160,000 direct cost for R01 grants would be unusual and require ample justification. FIRST (R29) awards are limited to $350,000 direct cost over the five year period. RESEARCH OBJECTIVES Investigations are needed that will lead to functional connections between existing fundamental knowledge gained from physiological studies and information yet to be obtained by utilizing cell and molecular biological techniques to directly address the pathophysiology of the glomerular portion of the nephron. Examples of diseases with disorders of the renal filtration barrier include: glomerulonephritis, Alport's disease, hypertension, and diabetic nephropathy. Responding applications should emphasize mechanisms rather than mere descriptions of processes. State-of-the-art biochemistry, and cellular and molecular biological techniques should be utilized in such investigations. The following are examples of projects/topics that would be responsive, but are not meant to present the full range of possibilities: o Studies that will provide an understanding of the maintenance of the differentiated phenotype by glomerular cells, mesangial cells and podocytes; o Receptor and mRNA localization studies on specific structures within the juxtaglomerular apparatus (macula densa, granular cells, etc.), especially not readily discernable or carefully probed in most autoradiographic or immunocytochemical studies; o Studies that will delineate more precisely the lineages of the glomerular endothelial and mesangial cells and podocytes; o Studies to delineate the relationship of cell-shape and basement membrane attachments in gene activation and maintenance of structural integrity capillary wall; o Studies to address transcriptional controls (both activation and deactivation) of basement membrane genes by glomerular cells; o Studies that will illuminate mechanisms of assembly of extracellular matrix molecules into the GBM, and mechanisms of GBM turnover; o Studies that will provide insight into the establishment of the glomerular microvasculature during organogenesis; o Studies that will provide new information concerning the mechanisms of mesangial matrix catabolism and its regulation; o Studies to delineate the role of growth factors, cytokines and hormones on the various glomerular cellular entities and GBM; o Studies to determine the acquisition of glomerular permselective sieving properties, and the relative contribution of endothelial and epithelial cells of these properties; o Studies on sex hormones and their receptors that may establish the mechanisms of gender based differences in glomerular cell biology and risk for glomerular disease; o Studies that will improve an understanding of the responses of glomerular cells and GBM to immune- and non-immune-mediated injury. 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 20, 1994 (FR 59 1450814513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. 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. ANIMAL WELFARE CONSIDERATIONS Investigators are encouraged to consider alternative methods and approaches in their research grant applications that do not require the use of whole animals, use alternative species such as nonmammals or invertebrates, reduce the number of animals required, and incorporate refinements to procedures that will result in the elimination or further minimization of pain and distress in animals. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: girg@drgpo.drg.nih.gov. The RFA label available in the PHS 398 (rev. 5/95) 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 program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. 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. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria o scientific, technical, or medical significance and originality of proposed research; 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. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. For Applications from Foreign Organizations: o availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or that provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds with other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review; o Availability of funds; o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues 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@ep.niddk.nih.gov Inquiries regarding fiscal matters may be directed to: Helen Y.S. Ling Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6An.44F, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8857 Email: lingh@ep.niddk.nih.gov 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 and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with PHS mission to protect and advance the physical and mental health of the American people. .
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