Metals in medicine.

The objective of this program announcement (PA) is to encourage research that bridges the areas of inorganic chemistry and medicine in continuation of PA-01-071. The National Institute of General Medical Science (NIGMS) is joined in this announcement by the N1EHS and the NIH Office of Dietary Supplements (ODS).

The mechanisms by which organisms control transition metal ions and the roles of these metals in cellular regulation and signaling in health and disease are of principal interest. The interactions of synthetic inorganic complexes with living systems and their components are an additional area of interest. These areas are linked by the need to involve researchers having a deep understanding of inorganic chemistry in medically relevant research. Much of the work is expected to involve collaborations including chemists, biologists, and medical researchers. The results will be relevant to understanding the mechanisms of metal handling by biological systems 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 involving metal complexes, although drug development, per se, is not a focus of the program.

A higher-order problem presents itself in understanding how the genome-encoded components and the other molecules are constituted in networks of" interacting molecules with particular distributions in time and space. Advances in imaging techniques and analytic methods are beginning to yield copious quantitative and spatial data on specific molecules in biological systems. Knowledge of the network and changes in its components over time, and the local rules by which the individual components distribute material and information, will substantially advance our knowledge.

Studies of metalloenzyme structure and function, mechanisms of action, and inhibition 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. In contrast, work in other areas of bioinorganic chemistry lags behind its potential application to human health. These areas include 1) mechanisms of metal metabolism as well as the roles of metals in regulation of cell function and cell-cell interaction, and 2) basic research toward diagnostic and therapeutic applications of metal complexes and of metal chelators and toward exploiting the unique properties of metals for therapeutic applications. The emphasis of this announcement is on the ions, complexes, and organometallic compounds of the transition metals known as lanthanides and actinides, post-transition metals, and metalloid elements.

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' disease, Wilson's disease, and hemochromatosis. Intercepting normal metalation reactions may be a way to control metalloprotein activity. Metals may also be associated with the pathology of protein aggregates such as those formed by prions and in Alzheimer's disease. Metals have also emerged as important sensors and transducers of information with roles in regulation and neurotransmission.

Areas of interest include 1) improved metal ion sensors to study cellular metal ion concentrations and localization; 2) reagents suitable to manipulate those concentrations; 3) identification and characterization of the macromolecular players and vesicular compartments involved in metal iota homeostasis and metal trafficking; 4) elucidation of the roles of metals in cell regulation, signal transduction, and cell-cell signaling; 5) identification and understanding of mRNAs and metal-, oxygen-, and redox-responsive transcriptional and translational regulators, and their potential as therapeutic targets; 6) elucidation of the mechanistic roles of essential trace elements for which metabolic functions are not yet clearly established; 7) analytical tools that accurately monitor biologically important pools, storage pools, and the chemical speciation of metals; 8) biomarkers of exposure and mechanisms of metal toxicity; 9) biomarkers for variable susceptibility to metal toxicity in the human population; and 10) chelation chemistry that can serve as the foundation for therapies to ameliorate aberrant metal accumulations and the effects of toxic exposures.

Interactions of Metal Complexes with Living Systems. The therapeutic application of metal complexes is an underdeveloped 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.

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, radiochemical properties) to measure and/or alter cellular functions. The actions of these compounds may provide insights that are different from those that can he 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. Principles are needed for the design of safe metal-containing therapeutics.

Another goal of this program is to utilize the power of inorganic chemistry to provide new knowledge of and new approaches for intervention in biological systems. Still 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.

Areas of interest include 1) reactions of metal complexes with cellular constituents (e.g., DNA, RNA, proteins, lipids, carbohydrates, redox substrates, signaling molecules); 2) reactions of metal complexes within the cellular milieu and in vivo; 3) uptake of metal complexes into cells and delivery to specific cellular compartments; 4) interactions of metal complexes with specific enzymes and receptors; 5) mechanisms by which synthetic metal complexes recruit cell cycle, signal transduction, and other metabolic pathways to alter cell functions; and 6) 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 listed in this PA.

Research encouraged by 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.

This funding opportunity will use the regular research (R01), exploratory research (R21), and program project (P01) award mechanisms. For a description of the R21 grant mechanism see http://grants.nih.gov/grants/funding/r21.htm. For descriptions of the P01 grant mechanism see http://www.nigms.nih.gov/funding/grntmech. Html#b (NIGMS) and http://www.niehs.nih.gov/ dert/programs/p01.htm (NIEHS).

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the nonmodular budget formats (see http://grants.nih.gov/grants/ fimding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions, available at http://grants1.nih.gov/grants/ funding/phs398/phs398.html in an interactive format. Otherwise, follow the instructions for nonmodular research grant applications. For further assistance, contact GrantsInfo at 301-435-0714 (telecommunications for the hearing impaired: TTY 301-451-0088) or by e-mail: [e-mail].

Applications must be prepared using the PHS 398 application instructions and forms (rev. 5/2001). Applications must have a Dun & Bradstreet (D&B) Data Universal Numbering System number as the universal identifier when applying for federal grants or cooperative agreements. This number can be obtained by calling 1-866-705-5711 or online at http://www. dnb.com/us/. The D&B number should be entered on line 11 of the Face page of the PHS 398 form. Applications must be submitted on or before the receipt date described at http://grants.nih.gov/grants/ funding/submissionschedule.htm. The complete version of this PA is available at http://grants.nih.gov/ grants/guide/pa-files/PA-05-001 .html.

Contact: Peter C. Preusch, Division of Pharmacology, Physiology, and Biological Chemistry, N1GMS, Bldg 45, Rm 2AS.43C, MSC 6200, Bethesda, MD 20892-6200 USA, 301-594-5938, fax: [phone], e-mail: [e-mail]; Claudia Thompson, NIEHS, DERT/OPD/CEMBB, MD EC-21, PO Box 12233, Research Triangle Park, NC 27709 USA, 919-541-4638, fax: [phone], e-mail: [e-mail]; Becky Costello, ODS, NIH, Bldg 31, Rm 1B25, MSC 2086, Bethesda, MD 20892-2086 USA, 301-435-2920, fax: [phone], e-mail: [e-mail]. Reference: PA No. PA-05-001