Full Text PA-96-043 LINEAGE-SPECIFIC DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS NIH GUIDE, Volume 25, Number 13, April 26, 1996 PA NUMBER: PA-96-043 P.T. 34 Keywords: Cancer/Carcinogenesis Biology, Cellular Biology, Molecular 0705048 National Institute of Diabetes and Digestive and Kidney Diseases National Cancer Institute PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), through its Division of Kidney, Urologic and Hematologic Diseases, and the National Cancer Institute (NCI), through its Cancer Immunology Branch, support fundamental and applied research aimed at understanding the fundamental processes underlying the normal and pathologic function of blood cells and the blood forming system. The processes of lineage-specific differentiation of the hematopoietic stem cells are central to the maintenance of normal hematopoiesis. An increased understanding of the molecular mechanisms controlling these events would increase our ability to combat selective cytopenias, and could facilitate hematopoietic reconstitution following radiation, chemotherapy, and marrow transplantation. Also, leukemias and lymphomas usually are regarded as hematopoietic cells frozen at various stages of differentiation. Elucidation of the basic mechanism of the differentiation process is important to our understanding of leukemogenesis and lymphomagenesis. 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 the 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 require ample justification. FIRST (R29) awards are limited to $350,000 direct cost over the five year period. RESEARCH OBJECTIVES The purpose of this PA is to promote the identification and characterization of the gene expression involved in hematopoietic cell regulation including, but not restricted to: (1) Stem cell self-renewal or commitment; (2) Expression of growth factor receptors as part of the commitment process of stem cells; (3) Developmentally-related changes in stem cell biology and differentiation. These studies should provide insight into the fundamental processes involved in the maintenance of the stem cell compartment and its production of committed progenitor cells through the lifespan of the organism. Applications are solicited that are centered around investigations into the mechanisms of gene regulation during hematopoietic cell maturation and differentiation. Of particular interest is the elucidation of specific DNA sequences, DNA binding proteins, signal transduction mechanisms, extracellular matrix proteins, and cell-surface proteins that influence gene expression. For instance, recently it has become evident that beta-2 integrins are not simply adhesion sites on the cell surface of hematopoietic cells but may modulate a number of cellular processes including signal transduction pathways and gene expression. Thus, integrins may be part of the signal transduction pathways that include growth factors, growth factor receptors, tyrosine kinases and phosphatases. Many opportunities for basic research exist in the control of the genes expressed in various hematopoietic lineages. A major development of the last ten years in understanding the differentiation of the erythroid lineage has been the discovery of the Locus Control Region that lies upstream of the beta-globin gene locus. This novel regulatory element activates the chromatin domain, confers erythroid lineage specific expression of linked genes, and is a powerful enhancer. The mechanism of action of this element remains unknown. Delineation will be important for achieving gene therapy of the beta-chain hemoglobinopathies. Other recently described regulatory elements also require investigation. Silencers have been identified for embryonic and fetal globin genes but the mechanism of their action is unknown. Recently, sequences which can insulate genes from the effects of surrounding chromatin have been identified. Delineation of these sequences and understanding their mechanisms of action will have a major impact on gene transfer technology. Trans-acting factors that control the developmental pattern of globin gene expression have been postulated on the basis of experimental data but their identities remain unknown. Other areas include the identification of new lineage-specific transcriptional factors or cell surface receptors, and their mechanisms of action. Little is known about the control of many of the known hematopoietic genes at the transcriptional level, including those for structural proteins, enzymes and receptors. A more complete understanding of the normal control of hematopoietic cell differentiation and the abnormal processes leading to pathogenesis will increase our understanding of hematologic diseases and will aid the development of rational therapies. 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 28, 1994 (FR 59 14508-14513) 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 Although this is a Program Announcement sponsored by the National Institute of Diabetes and Digestive and Kidney Disease and by the National Cancer Institute, 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 completeness by the Division of Research Grants (DRG). 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 will also 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 that IC. 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 either of the following: 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 AS-13C MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: David_Badman@nih.gov Grace L. Shen, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Room 501 Rockville, MD 20892-7381 Telephone: (301) 496-7815 FAX: (301) 496-8656 Email: Grace_Shen@nih.gov Inquiries regarding fiscal matters may be directed to either of the following: 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 Sara Stone Grants Management Branch National Cancer Institute 6120, Executive Boulevard, Room 243 Rockville, MD 20892 Telephone: (301)496-7800 X266 Email: Stones@gab.nci.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. .
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