Principal InvestigatodProgram Director _Last, first, middle): Dorshkind, Kenneth DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application, if the application is f_nded, this description, as is, will become public information. Therefore. do not include proprietary/confidential information. DO NOT E.XCEEO THE SPACE PROVIDED. B lymphopoiesis occurs in both fetal and adult life, but the patterns of development, the response of precursors to B lymphopoietic growth factors, and properties of the B cells generated differ.
The aim of this proposal is to identify B cell progenitors that emerge during embryogenesis and test the hypothesis that some of them persist into adult life where they contribute to postnatal immunity. Studies in aim 1 will investigate whether the developmental potential and cytokine responsiveness of phenotypically defined fetal B cell progenitor subpopulations are distinct from that of pro-B cells in postnatal bone marrow. A particular focus of these studies will be on a newly identified B220 (CD45R)-CD19+ fetal liver progenitor. These cells can generate macrophages and B cells that have characteristics that suggest they are B-1 B cells, such as co- expression of surface IgM, CD1 lb (Mac-l), and/or CD5. CD45R-CD19+ cells, which include a bipotential B/macrophage progenitor, are also present in adult bone marrow and can generate progeny with B-1 B cell characteristics. Various in vitro and in vivo approaches wilt be used in aim 2 to test the hypothesis that they are a self-renewing reservoir of fetal-derived B/macrophage progenitors that persist into postnatal life. The final series of experiments in aim 3 will examine the contribution of macrophages and B cells derived from the fetal and adult progenitors defined in aims 1 and 2 to the postnatal immune system. These studies will further characterize fetal B lymphopoiesis and are relevant to understanding the nature of B lymphoid progenitors in cord blood, which is being increasingly used as a source of hematopoietic donor cells. The data also have implications for understanding the origin of tumors with B/macrophage characteristics. PERFORMANCE SITE ========================================Section End===========================================
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