Full Text PA-97-036 BASIC RESEARCH ON THE METABOLISM OF IRON CHELATION NIH GUIDE, Volume 26, Number 4, February 7, 1997 PA NUMBER: PA-97-036 P.T. 34 Keywords: Metabolism, Mineral Pathophysiology Chemotherapeutic Agents Biochemistry National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The purpose of this program announcement is to stimulate basic research on the biochemistry of iron chelation in iron overloaded patients. Transfusional iron overload is a major cause of morbidity and mortality in patients with thalassemia (Cooley's anemia). These patients urgently need a safe, inexpensive, orally active chelating agent which effectively promotes iron excretion. This announcement seeks to encourage research applications which would improve the basic understanding of iron chelation, and thus would facilitate the development of new iron chelating drugs. 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 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 would require ample justification. FIRST (R29) awards are limited to $350,000 direct cost over the five year period. RESEARCH OBJECTIVES Considerable effort has been directed toward the development of a new oral iron chelator for the treatment of transfusional iron overload, particularly for patients with thalassemia (Cooley's anemia). However, the likelihood of success of this effort remains uncertain. Basic understanding of chelation needs to be improved in such aspects as the kinetics of iron chelation, the identity of the iron pools addressed, and ways to enhance the chelating activity and reduce the toxicity of known iron chelators. Renewed efforts are needed to learn more about the biochemistry of iron chelation in iron overloaded patients. Despite the lengthy and active search for an alternative to the only currently available drug, desferrioxamine B, only a few clinical trials of a limited nature have been conducted with new candidate drugs (Olivieri, et.al., 1995; al-Refaie, et.al., 1995). The important goal remains to further the understanding of those characteristics which would make an iron chelator effective and safe in long term use. More detailed analysis of the intracellular pharmacology of potential new chelators is needed, including organelle uptake and metabolism. Studies are needed which would help to identify more precisely the characteristics which determine efficacy and those which are associated with toxicity. Potential research topics are described below; however, investigators are invited to propose other topics for study. Pathophysiology of iron overload. There is still a remarkable gap in our knowledge of what determines the actual tissue damage or dysfunction. This may have direct relevance to the choice of chelator or the way it is administered. Some have postulated that if free iron has a major role, an effective chelator must have a constant presence in the bloodstream (Fosburg and Nathan, 1990). Harmful iron levels. Despite various constructs regarding the level of iron overload that is potentially harmful or definitely harmful, little is known about the degree of iron overload that is associated with organ damage in transfusional hemochromatosis. For example, the data on liver iron concentrations often used to determine the effectiveness of investigational chelators is drawn from the experience with primary hemochromatosis, a disease in which the major adverse outcome is cirrhosis, not heart failure as in thalassemia, so that the relevance is uncertain (Nielsen, et.al., 1996). Either animal models of transfusional iron overload or clinical, pathological, and biochemical correlates in humans would be helpful in addressing this issue. Measurement of iron overload. There are clear clinical needs in this area, since effective removal of iron by chelating drugs requires an accurate assessment of iron stores in the patient. Currently, there are three types of tests available, serum ferritin, biopsy, and the SQUID device, each with serious practical deficiencies. Serum ferritin, which is measured on drawn blood, is highly variable, and can be used only as a rough indication of the amount of stored iron. Biopsy of the liver results in accurate information, but can be performed only 1-2 times per year, at most, while biopsy of the heart is too risky. The SQUID device (Brittenham, et.al., 1982, Nielsen, et.al., 1995), whose development was funded by the NIDDK, gives accurate results for the liver, but there are only two such devices in the world, resulting in restricted access. Biochemical or physical methods such as MRI for iron determination need to be developed (Jensen, et.al., 1994). Particularly needed is a method for assessing cardiac iron. Investigation of the cellular origin, biochemistry, and regulation of serum ferritin. As alluded to above, despite the clinical importance of serum ferritin, the most fundamental aspects of its biogenesis, clearance, normal regulation, and mechanisms for observed pathological changes remain unknown. The molecular factors controlling ferritin biogenesis, release, and clearance via cellular uptake are unknown, and the molecular structure of serum ferritin and its relationship to other intracellular ferritins remains undefined. Because of the possibility that serum ferritin may remain the most practical means of assessment of iron status for some time to come, improved understanding of this protein is needed, including the molecular identification of the cDNAs and genes for serum ferritin, functional and biochemical properties associated with the protein, the characterization of its tissue origins, and the elucidation of the physiological control mechanisms regulating serum ferritin levels in normal and pathological conditions. 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 20, 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, or may be obtained from the Grants Information Office, 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 Applications will be assigned 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 also will 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 assigned to the National Institute of Diabetes and Digestive and Kidney Diseases. 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 6AS-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. References Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blandis LM, Cameron G, McClelland RA, Liu PP, Templeton DM, Koren G. Iron- chelation therapy with oral deferiprone in patients with thalassemia major, N Engl J Med 332(14):918-22, 1995. Al-Refaie FN, Hershko C, Hofbrand AV, Kosaryan M, Olivieri NF, Tondury P, Wonke B. Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Brit J Haematol 91(1):224-9, 1995. Fosburg, MT and Nathan DG. Treatment of Cooley's anemia, Blood 76(3): 435-444, 1990. Niederau C; Fischer R; Purschel A; Stremmel W; Haussinger D; Strohmeyer G, Long-term survival in patients with hereditary hemochromatosis, Gastroenterology 110(4):1107-19, 1996. Jensen PD; Jensen FT; Christensen T; Ellegaard J. Non-invasive assessment of tissue iron overload in the liver by magnetic resonance imaging, Brit J Haematol 87(1):171-84, 1994. Brittenham GM, Farrell DE, Harris JW, Feldman ES, Danish EH, Muir WA, Tripp JH, Bellon EM, Magnetic-susceptibility measurement of human iron stores, N Engl J Med 30;307(27):1671-5, 1982. Nielsen P, Fischer R, Engelhardt R, Tondury P, Gabbe EE, Janka GE, Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone, Br J Haematol 91(4):827-33, 1995. .
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