Immunobiology of B Cell Differentiation

B 细胞分化的免疫生物学

• 批准号: 7743745
• 负责人: KENNETH Allan DORSHKIND
• 金额: $ 37.19万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743745
• 关键词: Address; Adult; Autoimmunity; B cell differentiation; B-Cell Development; B-Lymphocytes; Blood Circulation; Bone Marrow; CD19 gene; Cell Lineage; Cells; Cytokine Receptors; Data; Dependency; Development; Embryo; Embryonic Development; Estrogens; Exhibits; Fetal Liver; Fetus; Gene Expression; Goals; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immunobiology; Immunologic Deficiency Syndromes; Interleukin-7; Laboratories; Lymphopoiesis; Maintenance; Mouse Strains; Mus; Organ; Pattern; Phenotype; Population; Process; Production; Public Health; Regulation; Resolution; Signal Transduction; Site; Specific qualifier value; Staging; Stem cells; Stimulus; TSLP gene; Testing; Tissues; Transcriptional Regulation; Wnt proteins; Yolk Sac; base; cytokine; embryo tissue; fetal; gain of function; leukemogenesis; progenitor; programs; public health relevance; research study; residence; response; transcription factor

DESCRIPTION (provided by applicant): Numerous studies have revealed differences in the transcriptional regulation of B lymphopoiesis in the embryo and the adult. In addition, B lineage cells isolated from fetal liver and adult bone marrow exhibit differential sensitivity to selected cytokines. The central hypothesis of this proposal is that these differences exist because B-1 progenitors and their progeny are the dominant B lineage cells present in the embryo and that the intra- and extra-cellular signals to which they respond are distinct from those that regulate the development of B-2 B cells. This premise is based on recent studies from our laboratory demonstrating that B-1 B cell progenitors, identified by their unusual Lin- CD45Rlow/- CD19+ phenotype, are the major B cell progenitor population present in the fetus. The goals of this proposal are to determine when and where in the embryo B-1 progenitors emerge and test the hypothesis that the regulatory controls operative on them are distinct from those in the B-2 lineage. Aim 1 will take advantage of recent advancements in the phenotypic resolution of B-1 and B-2 progenitors to define when and in which embryonic tissues B-1 and B-2 B specified progenitors appear and expand and test the hypothesis that B-1 B cells are part of the primitive wave of hematopoiesis. Experiments in Aim 2 will use loss and gain of function approaches in order to identify transcription factors whose expression is required for B-1 development and test the hypothesis that the transcriptional regulation of B-1 and B-2 development is distinct. Fetal and adult B lineage cells exhibit distinct responses to various micro environmental and systemic signals, and we propose that these differences are due to the differential effects of these stimuli on B-1 and B-2 progenitors. Testing this possibility is the goal of Aim 3. Taken together, the results form this study will provide a comprehensive picture of fetal B cell development that is of relevance to the fields of immunodeficiency, leukemogenesis, and hematopoietic stem cell transplantation. PUBLIC HEALTH RELEVANCE B cell development initiates during embryogenesis, but little is known about this process. The results obtained from the experiments in this application will provide a comprehensive understanding of fetal B lymphopoiesis that will be of relevance to the fields of immunodeficiency, autoimmunity, leukemogenesis, and hematopoietic stem cell transplantation.

描述（由申请人提供）：大量研究表明，胚胎和成人中B淋巴管的转录调控差异。另外，从胎儿肝脏和成年骨髓分离出的B谱系细胞对选定的细胞因子表现出差异的敏感性。该提议的中心假设是存在这些差异，因为B-1祖细胞及其后代是胚胎中存在的主要B谱系细胞，并且它们反应的细胞内和细胞外信号与调节B-2 B细胞发育的那些不同。该前提是基于我们实验室的最新研究，该研究表明，B-1 B细胞祖细胞的异常lin- CD45Rlow/-CD19+表型确定，是胎儿中存在的主要B细胞祖细胞群体。该提案的目标是确定胚胎B-1祖细胞中何时何地出现，并检验了以下假设：监管控制对其的调节控制与B-2谱系中的那些不同。 AIM 1将利用B-1和B-2祖细胞表型分辨率的最新进展来定义胚胎组织B-1和B-2 B指定的祖细胞的何时何地出现，并扩展并测试假设B-1 B细胞是造血的原始波的一部分。 AIM 2中的实验将使用功能方法的损失和增益，以识别其表达的转录因子，其表达是B-1开发所需的，并测试了B-1和B-2发育的转录调控的假设是不同的。胎儿和成人B谱系细胞对各种微环境和全身信号表现出明显的反应，我们建议这些差异是由于这些刺激对B-1和B-2祖细胞的差异作用。测试这种可能性是目标3的目标。总之，该研究的结果形式将提供胎儿B细胞发育的全面图片，这与免疫缺陷，白血病和造血干细胞移植有关的领域相关。公共卫生相关性B细胞开发在胚胎发生过程中启动，但对此过程知之甚少。从本应用中的实验中获得的结果将提供对胎儿B淋巴细胞的全面理解，这将与免疫缺陷，自身免疫性，白血病发生和造血干细胞移植有关。