INNOVATIVE USE OF NON-MAMMALIAN MODEL ORGANISMS TO STUDY MEMBRANE TRANSPORT Release Date: September 26, 2000 RFA: DK-01-012 National Institute of Diabetes and Digestive and Kidney Diseases National Institute of General Medical Sciences Letter of Intent Receipt Date: February 22, 2001 Application Receipt Date: March 22, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE Abnormalities in membrane transport processes are associated with many human diseases such as diabetes, cystic fibrosis, renal tubular acidosis, congestive heart failure (hypokalemia), and several intestinal disorders, all of which contribute to a major health care burden for the United States population. Many of these membrane transport processes are well conserved in lower organisms where the genomes are known, which are genetically tractable, and which are easily manipulated at the cellular and molecular levels. Unicellular organisms (bacteria, yeast) have been used as overexpression systems to provide quantities of wild-type or mutated proteins for structure/function studies, or as test tubes for regulatory studies. Similarly, non-mammalian model organisms such as Caenorhabditis elegans (C. elegans) and Drosophila melanogaster are more complex yet highly manipulable systems in which to understand the underlying mechanism, regulation, and protein structure of many evolutionarily conserved membrane transport processes. However, to fully exploit these model systems, new experimental technologies need to be developed and/or existing technologies need to be further refined. This initiative will provide Pilot and Feasibility grants (R21) to utilize non-mammalian models to develop reagents, methodologies, and novel approaches to the study of membrane transport, especially those membrane transport processes involved in diseases of relevance to NIDDK and especially those involved and required for normal cell function of interest to NIGMS. Examples of relevance to NIDDK include new highly differentiated cell lines (such as tubule cells), mutant organisms, electrophysiological or imaging methods to study transporter physiology and regulation in vivo; structure-function studies of purified homologous proteins or proteins in model membrane systems; identification of human homologues to proteins studied in model organisms, and the search for novel genes and proteins involved in membrane transport of ions and nutrients. Examples of interest to NIGMS include new vectors for the overexpression of membrane transporters and associated membrane proteins, refolding and purification strategies of overexpressed transporters and novel structural approaches to the elucidation of their structures. 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. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) exploratory pilot and feasibility project grant (R21) award mechanism. Responders to this initiative may be new or experienced investigators who are able to develop new and innovative approaches to study membrane transport proteins. Generally pilot and feasibility proposals are expected to have little preliminary data and are reviewed based on the development of hypotheses and supporting literature. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The maximum budget request for R21 applications may not exceed $100,000 in direct costs per year, and may not exceed two years for the total project period. This RFA is a one- time solicitation. The anticipated award date is September 30, 2001. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grants can be found at https://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NIDDK intends to commit approximately $2.5 million and the NIGMS $500,000 in FY 2001 to fund approximately 20-24 applications in response to this RFA. Although the financial plans of the IC(s) provide support for 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. RESEARCH OBJECTIVES Background Membrane transport is essential for almost all physiologic processes, and disruption often results in disease or death. New information, emerging from the study of bacterial genomes, has revealed a surprising degree of conservation of structure of many important membrane transporter families. A new classification system for transport proteins, based on gene sequences from twenty organisms and sorted by mode of transport and energy coupling mechanism, protein phylogenetic family, and substrate specificity, identified nearly 200 well- characterized families, and an additional 50 or more deemed incompletely characterized. Distinct categories include primary active transporters (23 families); secondary active transporters including uniporters, symporters, and antiporters (77 families); and channels and pores (115 families). Transporters facilitate entry of nutrients into the cytoplasm and subcellular compartments. Interestingly, several nutrients are now known to directly influence transporter gene expression. Transporters also provide mechanisms for homeostasis and regulation of metabolite concentrations by catalyzing the excretion of end products from cells and organelles. Transporter systems control concentrations of ions at levels significantly different from the extracellular milieu; the cell requirements of membrane potential, water and ion concentrations, and trace mineral co-factors are all dependent on transport mechanisms. Furthermore, these systems mediate the active extrusion and uptake of drugs and/or toxic substances through both the cytoplasm and cell membrane. Transporters also facilitate the uptake and release of a variety of signaling molecules, e.g. hormones, which define unique cellular function. Tremendous progress in molecular biology, genomics, and computer technology is resulting in advances in understanding protein structure, the substrates and mode of action of various membrane transporters, their regulation, and their impact on cellular and organ function. Much of this work has been done in bacteria, yeast and cultered cells. However, many problems remain to be overcome, and it is likely that prokaryotes and both lower and higher non-mammalian model systems, including C. elegans and Drosophila, will provide some solutions. Among other advantages, their genomes have been sequenced, and they are genetically manipulable. In addition, these organisms lack much of the genetic and molecular redundancy found in higher animals, simplifying the study of those transporters that are conserved with humans. Membrane protein structure studies are notoriously difficult because of insufficient quantities of pure protein, and because they are usually not readily crystallized. NMR is rarely used to determine structure because of the large size of these proteins; however, non-mammalian eukaryotic model organisms may contain homologues of important transporters that are more easily overexpressed and more easily crystallized, yet may be more similar to the mammalian proteins than those found in prokaryotes. In other cases, the prokaryotic model is the only one available and tractable for such studies. Important insights are also to be expected in studies of regulation of transporter activity or regulation via control of transcription at the protein level by enzymes or other protein cofactors, through changes in substrate affinity, by allosteric metabolites, or via compartmentation or movement through the cell. Changes in transporter activity can be in response to hormones, substrate delivery, or other complex processes. Regulation can therefore depend on interactions with other organs, on cell machinery or membrane composition, and can be difficult to study in far-removed model systems or in isolated cells. Many necessary tools, like genetic manipulation or fluorescence tagging are more difficult to use in intact mammals. Similarly, study of mutated model organisms or the sequenced genomes of a variety of organisms may yield information about unknown associated protein subunits or regulators. Objectives and Scope The purpose of this initiative is to provide Pilot and Feasibility grants to fund the development of tools and methods that permit the exploitation of non-mammalian model organisms to characterize membrane transport in areas of interest to NIDDK. The following are some examples of the types of investigations that would be responsive to this RFA; however, responses need not be limited to those areas listed below. o new strategies for finding novel transporters and their associated molecules; o development of isolated cell preparations and cell lines (such as renal tubule cells), from genetically tractable non-mammalian model organisms, especially those with sequenced genomes; o development of forward and reverse genetic strategies for characterizing membrane protein structure, function and regulation; o finding new means of utilizing mutant organisms for the study of membrane transport; o use of model organisms to study changing roles of transporters throughout development and among organs; o finding homologues of important mammalian genes that are more easily over-expressed and/or crystallized; o development of new methods that will lead to the characterization of ion channels and other ion transporters and their interacting proteins; o development or refinement of electrophysiological, electron microscopic or imaging methods to be used for assessing membrane transport function in the intact organism; o development and application of informatic tools for identifying membrane transport proteins and studying their function. It is anticipated that, as a result of the grants funded with this RFA, new and innovative approaches will have been developed and will be effectively utilized by the investigators to submit competitive investigator-initiated R01 research grant applications. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by February 22, 2001, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and 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 that it contains allows NIDDK staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) 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, or may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov; and on the internet at https://grants.nih.gov/grants/funding/phs398/phs398.html. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Budget Instructions Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $100,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. 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. The RFA label available in the PHS 398 (rev. 4/98) 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 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 sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three 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 Bethesda, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by March 22, 2001. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. 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. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK and NIGMS. 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 NIDDK in accordance with review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate National 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 the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the 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, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o Innovation: Does the project appear to likely develop novel tools, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences. 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 NIDDK programmatic issues to: M. James Scherbenske, Ph.D., Renal Physiology/Cell Biology and Kidney Centers Program Director DKUHD/NIDDK 6707 Democracy Blvd, Room 613 Bethesda, MD 20892-5458 Telephone: (301) 594-7719 FAX: (301)480-3510 E-mail: scherbensk@extra.niddk.nih.gov or Maren Laughlin, Ph.D., Metabolism Research Program Director DDEMD/NIDDK 6707 Democracy Blvd, Room 6101 Bethesda, MD 20892-5458 Telephone: (301) 594-8802 FAX: (301)480-3503 E-mail: LaughlinM@extra.niddk.nih.gov or Michael K. May, Ph.D. DDND/NIDDK 6707 Democracy Boulevard, Room 663 Bethesda, MD 20892-5458 Telephone: (301) 594-8884 FAX: (301)480-8300 E-mail: MayM@extra.niddk.nih.gov Direct inquiries regarding NIGMS programmatic issues to: Jean Chin, Ph.D. CBB/NIGMS 45 Center Drive, Room 2AS.19A Bethesda, MD 20892-6200 Telephone: (301) 594-2485 Fax: (301) 480-2004 E-mail: ChinJ@nigms.nih.gov Direct inquiries regarding NIDDK fiscal and administrative matters to: Mrs. Helen Y.S. Ling Division of Extramural Activities NIDDK 6707 Democracy Blvd, Room 629 Bethesda, MD 20892 Telephone: (301) 594-8857 FAX: (301) 480-3504 E-Mail: LingH@extra.niddk.nih.gov Direct inquiries regarding NIGMS fiscal and administrative matters to: Ms. Grace Tuanmu Division of Extramural Activities NIGMS 45 Center Drive, Room 2AS.55J Bethesda, MD 20892-6200 Telephone: (301) 594-5520 Fax: (301) 480-2554 E-mail: TuanmuG@nigms.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.821, 93.847, 93.848, 93.849. Awards are 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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 the PHS mission to protect and advance the physical and mental health of the American people.
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