PA-01-071: METALS IN MEDICINE

Department of Health
and Human Services (HHS)

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This Program Announcement expires on June 1, 2004, unless reissued. METALS IN MEDICINE Release Date: March 19, 2001 (see reissuance PA-05-001) PA NUMBER: PA-01-071 National Institute of General Medical Sciences National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Environmental Health Sciences Office of Dietary Supplements, Office of the Director, NIH THIS PA 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 PA. PURPOSE The objective of this program announcement is to encourage research that bridges the areas of inorganic chemistry and medicine. The mechanisms by which organisms control transition metal ions and the roles of these metals in cellular regulation and cell-cell signaling are of primary interest. The interactions of synthetic inorganic complexes with living systems and their components are a second area of interest. These areas are linked by the need to involve researchers having a deep understanding of inorganic chemistry with state-of-the- art problems in biomedical research. Much of the work is expected to involve collaborations between chemists and biochemists and cell and molecular biologists. The results will be relevant to understanding the mechanisms of metal toxicity and the basic cellular roles underlying the nutritional requirement for essential metals. It is expected that this research will also contribute to the identification of new targets for drug discovery, diagnostics, and future therapeutic approaches, although drug development, per se, is not a focus of the program at this time. 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. This Program Announcement (PA), Metals in Medicine, is related to one or more of the 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 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISMS OF SUPPORT This PA will use existing National Institutes of Health (NIH) research project grant (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. 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 Grant applications can be found at: http://grants.nih.gov/grants/funding/modular/modular.htm Some research efforts may be more appropriate for the Program Project (P01) grant mechanism or the Resource-Related Research Project (R24) grant mechanism. Investigators interested in applying for P01 or R24 grants should contact the Institute program staff listed at the end of this announcement. RESEARCH OBJECTIVES The objective of this program announcement is to stimulate additional research in selected areas of bioinorganic chemistry. The emphasis of this announcement is on the ions, complexes, and organometallic compounds of the transition metals, post-transition metals, and metalloid elements. Based on input from a broad scientific community, NIH held a meeting, entitled, "Metals in Medicine: Targets, Diagnostics, and Therapeutics", on June 28 & 29, 2000. For the program and meeting report see: http://www.nigms.nih.gov/news/meetings/metals.html. The goals of this meeting were: 1) to explore the current utilization of inorganic chemistry and of basic research discoveries in metallobiochemistry by the pharmaceutical industry; and 2) to identify areas where additional basic research might enhance the impact of NIH support in these areas of science on future health improvements. Conclusions from this meeting were in brief: Metalloenzyme structure/function, mechanism, and inhibition studies are currently well supported and produce results that are utilized in the design of new diagnostic and therapeutic products. Additional stimulation of this area is not needed. Metal-containing agents for radiology, radiation therapy, and magnetic resonance imaging are expanding areas of activity that will benefit from further basic research on metal complexation chemistry and the interactions of metal complexes with biological systems. (Note: These areas are primarily the responsibility of the National Cancer Institute and will not explicitly be considered further in this announcement.) Metal metabolism is an area ripe with opportunities for additional research. Mechanisms of metal homeostasis as well as the roles of metals in regulation of cell function and cell-cell interaction are areas of potential growth. Therapeutic applications of metal complexes is an under-developed area of research. Basic principles to guide the development of metallopharmaceuticals are lacking. Metal-containing agents may offer unique therapeutic opportunities. However, significant obstacles, including potential metal accumulations and toxicities, require further research before the promise of medicinal inorganic chemistry can be realized. Based on this meeting and other sources of information, NIGMS, NIDDK, NIEHS, and ODS/NIH seek to stimulate additional applications in the following areas of research. A. Emerging Areas of Metal Metabolism and Regulation. Metal metabolism is emerging as an exciting area of cell biology and a potential area for therapeutic intervention. Normal metal metabolism appears to maintain free metal ion concentrations at a very low level and to deliver metals very selectively to their sites of action, while maintaining tight control over their reactivity. Aberrant metal metabolism contributes to pathological conditions such as Menkes' and Wilson's diseases, and hemochromatosis. Intercepting normal metalation reactions may be a way to control metalloprotein activity. Metals have also emerged as important sensors and transducers of information with roles in regulation. Areas of interest include: o Improved metal ion sensors to study cellular metal ion concentrations and localization. o Reagents suitable to manipulate those concentrations. o Identification and characterization of the macromolecular players and vesicular compartments involved in metal ion homeostasis and metal trafficking. o Elucidation of the roles of metals in cell regulation, signal transduction, and cell-cell signaling. o Identification and understanding of metal-responsive, oxygen, and redox responsive transcriptional and translational regulators, and mRNAs and their potential as therapeutic targets. o Elucidation of the mechanistic roles of essential trace elements for which metabolic functions are not yet clearly established. o Analytical tools that accurately monitor biologically important pools, storage pools, and the chemical speciation of metals. o Biomarkers of exposure and mechanisms of metal toxicity. o Biomarkers for variable susceptibility to metal toxicity in the human population. o Chelation chemistry that can serve as the foundation for therapies to ameliorate aberrant metal accumulations and the effects of toxic exposures. Basic research is needed to underpin recommendations regarding the nutritional importance of metal ions in the diet. Opportunities for research on zinc were highlighted at a meeting organized by the Office of Dietary Supplements (ODS), Office of the Director, NIH, and held on the NIH campus, Nov. 4-5, 1998. The proceedings of the meeting were published in the Journal of Nutrition, Vol. 130(5s), 1341S-1519S, May, 2000. A report of the meeting is available on the ODS web site. See: http://ods.od.nih.gov/showpage.aspx?pageid=129. Opportunities for research on chromium were highlighted at another meeting, also organized by the Office of Dietary Supplements, NIH, and held on the NIH campus, November 4, 1999. For a report see: http://odp.od.nih.gov/ods/news/conferences/chromium_diabetes.html. Of particular priority for the NIDDK is research in the areas identified as the most productive in accelerating progress relevant to the use of chromium supplements in individuals at risk for, or diagnosed with, diabetes. The mechanisms of uptake, metabolism, and storage of iron, particularly with regard to iron overload and iron chelation, also are of considerable priority to the NIDDK. Areas of interest were represented at the September 1998 NIDDK meeting Iron: From Current Biochemistry to New Chelator Development Strategies . For the abstracts of this meeting see: http://www.niddk.nih.gov/fund/reports/abstract.pdf. These examples are meant to be illustrative and not meant to single out these specific metals as being of exclusive interest. Similar questions about basic understanding of the roles of metals may be raised with respect to many other of the essential trace elements. The Office of Dietary Supplements, the NIDDK, and other components of the NIH have primary responsibility with respect to human nutritional value of metals. Both NIGMS and NIDDK have a high level of interest in understanding the mechanistic roles of essential dietary elements in molecular and cellular function. NIEHS has primary responsibility with respect to toxic metal exposure from environmental sources. Both NIGMS and NIEHS have interests in understanding the basic mechanisms of metal toxicity. B. Interactions of Metal Complexes with Living Systems. Metal complexes may be useful as research probes of biological function, as intermediary lead compounds in the development of non-metal containing therapeutics, and as potential diagnostic and therapeutic agents. Opportunities exist to exploit the unique properties of metal complexes, (e.g., hydrolytic and redox activity, Lewis acidity, electrophilicity, valency, geometry, magnetic, spectroscopic, and radiochemical properties) to measure and/or to alter cellular functions. The actions of these compounds may provide insights that are different from those that can be achieved through other chemical, biochemical, or genetic manipulations. Similarly, the actions of metal complexes in whole living organisms are expected to differ in general from the actions of non-metal containing agents and may offer unique research, diagnostic, or therapeutic opportunities. A goal of this program announcement is to utilize the power of inorganic chemistry to provide new knowledge of biological systems. Another goal is to improve understanding of the reactions of metal complexes in living systems to improve the specificity of these interactions and gain control over the potential toxicity of synthetic metal complexes. The long-term goal is to establish the basic principles of an inorganic medicinal chemistry that will allow for rational design and screening of potential metallopharmaceuticals in the future. Drug development, per se, is not the primary focus of the program at this time. Areas of interest include: o Reactions of metal complexes with cellular constituents, e.g., DNA, RNA, proteins, lipids, carbohydrates, redox substrates, and signaling molecules. o Reactions of metal complexes within the cellular milleu and in vivo. o Uptake of metal complexes into cells and delivery to specific cellular compartments. o Interactions of metal complexes with specific enzymes and receptors. o Mechanisms by which synthetic metal complexes recruit cell cycle, signal transduction, and other metabolic pathways to alter cell functions. o Structure/activity relationships for ligand design to control metal complex activity and stability in vitro and in vivo. The NIH Metals in Medicine meeting report includes a list of specific research opportunities and challenges. This list is intended to be illustrative, not exhaustive. Investigator-initiated ideas are welcome on any subject that will contribute to the objectives of this program announcement. Research responsive to this announcement may utilize any appropriate experimental organisms or model systems. For some problems, interesting discoveries may be found in microorganisms from unusual environments and atypical experimental organisms. For other problems, yeast, common invertebrate and vertebrate model organisms, and human cell/tissue cultures may be appropriate. Investigators considering human clinical trials are strongly encouraged to contact the program staff listed under Inquiries below. 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. APPLICATION PROCEDURES 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. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) 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 $250,000) 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 http://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. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. 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: http://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. 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 and 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. An applicant planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard 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 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. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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 The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Additional specific review criteria apply to program project, SBIR and STTR, and NIGMS INTEGRATIVE AND COLLABORATIVE APPROACHES TO RESEARCH award mechanisms. See the relevant announcements listed above for details. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and 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: Dr. Peter C. Preusch Division of Pharmacology, Physiology, and Biological Chemistry National Institute of General Medical Sciences Building 45, Room 2AS.43C Bethesda, MD 20892-6200 Telephone: (301) 594-5938 FAX: (301) 480-2802 Email: preuschp@nigms.nih.gov Dr. Maren R. Laughlin Director, Metabolism Program National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Rm. 6101, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8802 FAX: (301) 480-3503 Email: maren.laughlin@nih.gov Dr. Claudia Thompson National Institute of Environmental Health Sciences DERT/OPD/CEMBB MD EC-21, P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-4638 FAX: (919) 541-4606 Email: thompso1@niehs.nih.gov Dr. Becky Costello Office of Dietary Supplements National Institutes of Health Building 31, Room 1B25 Telephone: (301) 435-3920 FAX: (301) 480-1845 Email: costellb@od.nih.gov Direct inquiries regarding fiscal matters to: Mr. Joe Ellis Grants Management Officer National Institute of General Medical Sciences Building 45, Room 2AN.24C Bethesda, MD 20892-6200 Telephone: (301) 594-5135 FAX: (301) 480-2554 Email: ellisj@nigms.nih.gov Ms. Cheryl Chick National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 606 MSC 5458 6707 Democracy Blvd. Bethesda, MD 20892-5458 For Courier service, use Zip Code 20817 Telephone: (301) 594-8825 FAX: (301) 480-3504 Email: chickc@extra.niddk.nih.gov Mr. Dwight Dolby National Institute of Environmental Health Sciences DERT/OPO/GMB MD EC-22, P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-7824 FAX: (919) 541-2860 Email: dolby@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.821, 93.859, 93.862 for NIGMS, 93.113 for NIEHS, and 93.847, 93.848, 93.849 for NIDDK. Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 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 Office of Dietary Supplements (ODS) was mandated by Congress in 1994 and established within the Office of the Director, National Institutes of Health (NIH). The Dietary Supplement Health and Education Act (DSHEA) [Public Law 103-417, Section 3.a] amended the Federal Food, Drug, and Cosmetic Act to establish standards with respect to dietary supplements . This law authorized the establishment of the ODS. 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, and 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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