RENAL EPITHELIAL ION TRANSPORT MECHANISMS UNDERLYING DISEASE NIH GUIDE, Volume 23, Number 21, June 3, 1994 PA NUMBER: PA-94-071 P.T. 34 Keywords: 0715133 Pathophysiology 0765014 Membrane Structure/Function Biology, Cellular Biology, Molecular National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) encourages research grant applications for support of studies on the identification, description and characterization of renal tubular epithelial ion transport mechanisms that may underlie pathophysiological states. The objective is to promote research at the molecular and cellular level to better understand aberrations in renal epithelial transport mechanisms that may lead to disease states. The 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. These studies provide the basis for studies on the underlying mechanisms of kidney disease. This program includes studies utilizing whole kidney and/or the selected segments of the kidney or individual cells or any of their subcellular components as models. Those studies involving individual tubular segments, isolated cells and their component membranes have extended our knowledge of ion transport processes in the normal kidney, but still lacking is a comprehensive understanding of the many factors that govern body electrolyte balance and associated disease states. Nevertheless, the interactive play among receptors, modulatory proteins, phospholipid metabolites and second messengers is now becoming more clear in the modulation of ion transport, cytoskeletal organization, and growth and differentiation of the kidney. There are cellular and molecular biologic techniques that make it possible to identify and clone genes and proteins within renal epithelial cells responsible for anionic and cationic transport processes. 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 "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 non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) individual research 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 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 directly addressing the pathophysiology in various renal tubular epithelial diseases. Examples of diseases with disorders of epithelial transport include: renal tubular acidosis, gout, cystinuria, nephrogenic diabetes insipidus, polycystic kidney disease and Fanconi and Bartters syndromes. Responding applications should emphasize mechanisms rather than mere descriptions of processes. State-of-the-art biochemistry, and molecular and cellular 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 The mechanisms underlying the involvement of specific ion solute and water transporters in hereditary kidney disease, such as polycystic kidney disease, cystinuria, nephrogenic diabetes insipidus or hereditary disorders of urinary proton, phosphorous, calcium and uric acid excretion. o The mechanisms underlying the involvement of specific ion solute and water transporters in acquired kidney disease, such as obstructive nephropathy, hyperaldosteronism, or drug-induced nephropathy. o The aberrant regulation by systemic hormones, intracellular second messengers, phospholipid metabolites, or ions in the expression and activities of different renal ion and solute transport systems. o Role and mechanism of action of analogs and/or antagonists of specific transport systems or hormones/growth factors/cytokines or their receptors in treatment of kidney disease. o Studies of immunohistochemistry and in situ hybridization in human biopsies of the pathophysiological basis of abnormal urinary K+, Na+, Cl-, PO4, and H2O excretion. o Identification and functional significance of mutated genes whose expression is regulated by signal transduction through systemic hormones, growth factors, or other modulators in dysregulated endocrine or transport function. o The mechanisms underlying hypertrophy and upregulation of transport mechanisms in the renal response to partial loss of functioning nephrons. STUDY POPULATIONS 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 9, 1994 (FR 59 11146-11151) 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 Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the regular application deadlines for new research grant applications. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institute of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The title and number of this program announcement must be typed in Section 2a on the face page of the application. The earliest possible award dates will be approximately nine months after the respective receipt dates. Applications received too late for one review cycle will be held until the next receipt date. Applications for FIRST awards (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. Applications will be received by the NIH Division of Research Grants (DRG) and referred to an appropriate study section for scientific and technical merit review. Institute assignment decisions will be governed by normal programmatic considerations as specified in the NIH referral guidelines. Following scientific-technical review, the applications will receive a second-level review by an appropriate national advisory council. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institute of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS The review criteria customarily employed by the NIH for research grant applications and FIRST awards will prevail. Following the initial scientific review, those applications recommended for further consideration will be evaluated by the appropriate National Advisory Council. AWARD CRITERIA Applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases will compete for available funds with all other approved applications assigned to the Institute. 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 balance among research areas of the announcement INQUIRIES Written, email, and telephone 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 Westwood Building, Room 3A-04A Bethesda, MD 20816 Telephone: (301) 594-7522 Inquiries regarding fiscal matters may be directed to: Helen Y. Ling Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 639 Bethesda, MD 20816 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. .
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