Full Text PA-97-076 IMMUNOLOGICAL ASPECTS OF HEMATOPOIETIC STEM CELLS NIH GUIDE, Volume 26, Number 24, July 25, 1997 PA NUMBER: PA-97-076 P.T. 34 Keywords: Immune System Disorders Autoimmunity Immunology PURPOSE The National Institutes of Health (NIH) invites applications for studies of the early stages of lymphoid lineage commitment and development from hematopoietic stem cells. Although much has been learned in recent years to enhance understanding of the later stages of T, B and natural killer (NK) cell development, definition of the complex processes that regulate lymphoid lineage commitment and early lymphoid progenitor cell differentiation requires expanded research efforts. Work in this area is expected to provide basic information needed for future applications to human immunodeficiency diseases, autoimmune diseases, hematopoietic stem cell transplantation and gene transfer therapy. HEALTHY PEOPLE 2000 Each NIH PA addresses one or more of 22 Health Promotion and Disease Prevention priority areas identified. These areas can be found via the WWW at URL: http://www.crisny.org/health/us/health7.html ELIGIBILITY 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) awards (R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01) and FIRST Award(R29) applications may be submitted in response to this announcement. Applications for R01 grants may request up to five (5) years of support; applications for R29 grants must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background Circulating blood cells, including the B, T and NK cells of lymphoid lineage, continuously turn over, and must be regenerated from uncommitted, pluripotent hematopoietic stem cells, which are located in fetal blood, umbilical cord blood and adult bone marrow. These stem cells are capable of both self-renewal and differentiation along complex pathways to generate the lymphoid, myeloid, monocyte, erythroid and megakaryocyte lineages of mature, functional cells. Although recent results have begun to define some of the critical events in lymphopoiesis, much remains to be learned about the tightly regulated combination of factors that direct the initial commitment of hematopoietic stem cells to the lymphoid lineage, and the subsequent events that determine which mature lymphoid lineage, B, T or NK cell, is produced. It is known that key decisions made during lymphopoiesis depend on a multitude of signals derived from cell:cell interactions, soluble factors, and the extracellular matrix within stromal microenvironments at specialized sites of maturation. Inappropriate signals at any stage during this process might result in defective immune system development and the consequent loss of vital immune functions. Recent progress in achieving successful stem cell engraftment across histocompatibility barriers suggests that stem cell transfer will become an increasingly utilized therapy for a variety of conditions. Furthermore, the potential for genetic manipulation of hematopoietic stem cells to correct immune defects underscores the need to understand the mechanisms by which gene expression is regulated during lymphopoiesis, in order to design vectors for gene therapy that can be targeted for expression at appropriate developmental stages in restricted cell lineages. Identification of cytokines, receptors and signaling molecules involved at distinct and critical stages of lymphocyte development would allow production of therapeutic agents to enhance specific lineage development or function. Techniques for the isolation and characterization of human, non-human primate and rodent hematopoietic stem cells and early lymphoid progenitor cells are being defined, and certain markers that identify stages in lymphoid lineage commitment have been described. It is known that in some diseases, such as HIV infection, there is damage to stem cells or their microenvironment that prevents normal engraftment and differentiation. It is currently feasible to obtain a more definitive understanding of lymphopoiesis using both in vitro and in vivo approaches, and to use this information for stem cell therapy in human disease. Research Objectives and Scope A more complete definition of the integral stages of early B, T and NK cell development will increase our understanding of the genesis of the immune system, and will provide critical information needed for therapeutic intervention mediated by stem cell transplantation, gene transfer or immunotherapy. Innovative, multidisciplinary approaches that include molecular genetics, biochemistry, cell biology and whole animal studies are encouraged. Examples of research areas of interest include, but are not limited to: o phenotypic markers of lymphoid progenitor cells at different stages of development; o cell:cell or cell:microenvironment interactions that are critical for lymphopoiesis; o the effect of defects in the stromal environment on the growth and differentiation of stem cells, and methods to overcome or correct these defects; o the role of soluble molecules and their receptors in triggering or suppressing lymphoid lineage differentiation; o signal transduction pathways involved in key lymphoid differentiation decisions; o transcription factor regulation during lymphopoiesis; and o interdependence of differentiation pathways for lymphoid lineage development. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS See NIH Guide of March 18, 1994 for requirements for inclusion of Women and Minorities in research. It is available via the WWW at URL: http://www.nih.gov/grants (select NIH Guide for Grants and Contracts). APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted on the standard application deadlines as indicated on the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title, "IMMUNOLOGICAL ASPECTS OF HEMATOPOIETIC STEM CELLS," must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application 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 20817-7710 (for express/courier service) R29 applications must include at least three (3) sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applicants from institutions that have a General Clinical Research Centers (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants. Incomplete applications will be returned to the applicant without further consideration. 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. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance, and availability of funds. INQUIRIES Each sponsoring Institute/Center is identified below. A staff contact for electronic and telephone is listed and inquiries regarding programmatic (research scope, eligibility and responsiveness) issues are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. National Institute of Allergy and Infectious Diseases Helen Quill, Ph.D. Telephone: (301) 496-7551 Fax: (301) 402-2571 EMAIL: hq1t@nih.gov National Institute on Aging Dr. Anna M. McCormick Telephone: (301) 496-6402 Fax: (301) 402-0010 EMAIL: am38k@nih.gov National Heart, Lung and Blood Institute Dr. Alan Levine Telephone: (301) 435-0050 Fax: (301) 480-0868 EMAIL: al20y@nih.gov National Institute of Diabetes and Digestive and Kidney Diseases David G. Badman, Ph.D. Telephone: (301) 594-7717 Fax: (301) 480-3510 EMAIL: David_Badman@nih.gov AUTHORITY AND REGULATIONS Research under this announcement will be supported under program cited in the Catalog of Federal Assistance (CFDA). The PHS portion of the CFDA is available at URL: http://odphp.osophs.dhhs.gov/cfda/index.htm. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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