Full Text PA-96-055 SMALL MOLECULE TRANSPORTER PROTEINS IN BLOOD, RENAL AND PROSTATE CELLS NIH GUIDE, Volume 25, Number 18, June 7, 1996 PA NUMBER: PA-96-055 P.T. 34 Keywords: Hematology Biology, Cellular Membrane Structure/Function 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, supports fundamental and applied research aimed at understanding the fundamental processes underlying the normal and pathologic function of blood cells and the blood forming system. Also supported is 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. Urologic research is supported, including cellular and molecular approaches to the study of tissue-specific and cell-specific regulation of prostate growth. The ability to maintain a constant systemic environment is a critical requirement to maintain the normal health of an organ. At the cellular level, specific transport pathways maintain both the intracellular environment as well as providing the mechanisms that drive the maintenance of systemic balance. Cellular transport is mediated by specific membrane proteins. To understand the physiology and pathophysiology of homeostatic balance requires an understanding of how they are regulated. Methods for identifying and isolating the proteins or the genes for the proteins are available using contemporary cellular and molecular biological approaches. Such approaches have been used successfully to isolate a number of transporters from kidney, prostate, red blood cells, and other cells, making it possible to understand normal homeostatic mechanisms, as well as those leading to pathology of the homeostatic system. 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 proposed 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 Examples of applications responsive to the announcement include: (1) development of integrated programs to study the structure and function of the different transport proteins that are expressed in the red cell, prostate, and the kidney; (2) molecular biological approaches to study tissue specific expression of the various isoforms of the proteins; (3) development of information on structural biology of the proteins; (4) immunochemical localization of different proteins in various blood, renal and prostatic cells; (5) functional analysis of the proteins using tissue-specific knockout strategies; (6) definition of mutations responsible for human diseases; (7) definition of the functional consequences of protein-protein interactions in the membrane, and of membrane protein-cytoskeletal interactions; (8) the study of lipid-protein interactions, such as membrane microdomains; and (9) the study of the regulation of transport protein function by accessory molecules that act as regulators of these transporters under various pathophysiological conditions. Fundamental information has been accumulated on the molecular architecture of the red cell membrane skeleton. It is becoming increasingly clear that red cell structural proteins and their isoforms are present in a wide variety of cells, including epithelial and endothelial cells. Knowledge of the dynamics of protein-protein interactions in the red cell membrane is likely to contribute to our understanding of the structure and function of plasma membranes of nucleated cells. Red cell blood group antigens are epitopes on membrane-spanning proteins whose functions may include anion exchange (Band 3--ABH antigens and Diego antigens), water transport (Colton antigens), urea transport (Kidd antigens), degradation of circulating peptide hormones (Kell antigens), removal of circulating chemokines (Duffy antigens), or possibly provision of structural supports for localized lipid environments (Rh antigens). Several of these proteins have been identified also in renal tubules. There also has been a recent rapid increase in information on the identification and isolation of small molecule transporters in kidney and similar epithelia. Some examples are the Na/Cl and Na/K/Cl cotransporters, Na, K, and Ca channels, N/H antiporters, hormone receptors in the prostate, and Na/Cl exchangers. An integrated approach linking the biochemical and molecular genetic information derived from red cell studies with the sophisticated physiological analyses of microdissected renal tubules and highly resolved distributional studies in kidney and prostate are likely to provide major insight into this new area of biology. Moreover, detailed molecular and clinical analysis of human null phenotypes of each of these antigenic groups may be very instructive, since many could turn out to be equivalent to gene knockouts. Similarly, knowledge derived from study of white blood cells offers the opportunity to learn more about transport functions, signal transduction, membrane-trafficking, cell transfection (particularly in lymphocytes), genetic diseases, and adhesion molecules. Interaction of investigators with expertise in blood cell membrane physiology and investigators in kidney and/or prostate epithelial cell biology is particularly encouraged. 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 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 Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the 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: asknih@odrockm1.od.nih.gov. 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. Potential R29 applicants should refer to the announcement on Just-in-Time Procedures for FIRST and Career Awards (NIH Guide for Grants and Contracts, Vol. 25, No. 10, March 29, 1996)) for information on recent changes in guidelines for FIRST award format. 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 Although this is a Program Announcement sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute also has an interest in the subject matter of this PA. Other Institutes/Centers of the NIH also may have an interest. Applications will be assigned to the most appropriate Institute/Center 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. 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: David G. Badman, Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room AS-13C MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: David_Badman@nih.gov Inquiries regarding fiscal matters may be directed to: Aretina Perry Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-38B, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8862 Email: PerryA@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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