BASIC RESEARCH ON HEMATOPOIETIC GENE REGULATION NIH GUIDE, Volume 22, Number 43, November 26, 1993 PA NUMBER: PA-94-015 P.T. 34 Keywords: Hematology Gene Regulation Biology, Cellular National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The purpose of this Program Announcement (PA) is to encourage research grant applications related to the mechanisms of hemopoietic gene regulation and of differential gene expression during hematopoietic cell maturation and differentiation. 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. This PA, Basic Research on Hemopoietic Gene Regulation, is related to the priority area of diabetes and other chronic disorders. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). 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. Applications from minority individuals and women are encouraged. MECHANISMS OF SUPPORT Support of this program will be primarily by research project grants (R01) and FIRST awards (R29). Deadlines for new grants are February 1, June 1, and October 1, and for competing and revised grants are March 1, July 1, and November 1. Because the nature and scope of the research applications submitted in response to this Program Announcement may vary, it is anticipated that the size of award will vary also; however, the average size is estimated to be approximately $200,000 total costs. RESEARCH OBJECTIVES The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) supports basic and clinical studies related to hematopoiesis and the process of lineage-specific differentiation of the hematopoietic stem cell. These processes are central to the maintenance of normal blood cell counts, and to the reconstitution of blood counts following bone marrow insults, such as infections, radiation and chemotherapy. An increased understanding of the specific molecular mechanisms underlying lineage-specific differentiation processes could enhance our ability to combat selective cytopenias, and facilitate bone marrow reconstitution following bone marrow transplantation. Areas of research interest under this announcement include, but are not limited to, investigations into the mechanisms of hematopoietic gene regulation and of differential gene expression during hematopoietic cell maturation and differentiation. Of particular interest is the elucidation of factors such as DNA elements, DNA binding proteins, nuclear matrix, signal transduction mechanisms, stromal or cell-surface protein interactions that may contribute to lineage-specific differentiation by modulation of gene expression. The alpha- and beta-globin gene clusters serve as examples of an area of hematopoiesis that has developed greatly in the past few years. Most of the regions of the human chromosomes containing the genes for hemoglobin, defective in Cooley's anemia and sickle cell disease patients, have been sequenced. The characterization of relevant DNA regions and DNA-binding proteins is well along. The role of the DNA within the genes, as well as in the genetic regions that control the DNA, is now understood to a considerable extent. This information has been of considerable value in explaining the normal developmental control of these genes, as well as the abnormal states that exist in the hemoglobin disorders. Regions of DNA linked to both clusters of hemoglobin genes determine developmental expression, and may be intimately involved in the switch in hemoglobin formation which occurs at the time of birth in humans and in many animals. Other regulatory factors, either closely linked to genes or on other chromosomes, have been found to control the expression of the genes. Much still remains to be learned about gene regulation and switching of expression from one gene to another at various stages of human development, including the mechanism of action of drugs such as hydroxyurea and butyrate, which have been shown to enhance fetal hemoglobin formation, thus lending themselves as possible therapeutic agents for the globin gene disorders. The recent cloning of the gene for the hormone erythropoietin and the gene for the erythropoietin receptor, for humans and other species, has opened up the study of this aspect of the erythroid component of hematopoiesis. The cloning of other cytokines and their receptors continues rapidly, as well, promising clarification of many aspects of hematopoiesis, as well as providing other drugs for clinical use. The molecular mechanisms of these hormone-cell interactions are being studied at the level of receptor binding, internalization, signal transduction, and apoptosis. Similarly, new techniques using cell surface molecules and monoclonal antibodies, are allowing identification of various precursor cell populations, including cells which may constitute the hypothetical totipotent hematopoietic stem cell. Characterization and preparation of these stem cell and precursor cells in large quantities would be of major importance in the application of this new knowledge to clinical situations. New techniques including transgenic animal expression systems, "knock out" animal models (frequently using embryonal cells), PCR assays, homologous genetic recombination, transient and stable cell expression systems, and YAC and other large DNA cloning vectors, are allowing the field of molecular hematopoiesis to develop very rapidly. Whereas much of the previous work has used mouse and other animal models, these new techniques are facilitating more direct analyses of human genes and cells. This Program Announcement is intended to stimulate a broad range of new research programs in the general area of regulation of genetic processes involved in hematopoietic cell differentiation. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions that disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups must be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) 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 Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The title and number of this announcement must be typed in line 2a on the face page of the application. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or Principal Investigator could be included with the application. Applications for R29 awards must include at least three letters of reference attached to the face page of the original application. Applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** 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 will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by an appropriate national advisory council or board. Applications for supplements to ongoing awards will be reviewed according to procedures applicable to the mechanism of the ongoing award. AWARD CRITERIA Applications will compete for available funds with all 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 balance among research areas of the announcement INQUIRIES Written and telephone 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 Westwood Building, Room 3A-05 Bethesda, MD 20892 Telephone: (301) 594-7541 Direct inquiries regarding fiscal matters to: Ms. Trude McCain Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 649 Bethesda, MD 20892 Telephone: (301) 594-7543 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. 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. .
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