SIGNAL TRANSDUCTION IN B CELL ACTIVATION

B 细胞激活中的信号转导

• 批准号: 3132101
• 负责人: John C Cambier
• 金额: $ 12.87万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1988-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3132101
• 关键词: B lymphocyte; high performance liquid chromatography; histocompatibility antigens; immunoglobulin D; immunoglobulin M; leukocyte activation /transformation; lipid metabolism; membrane activity; monoclonal antibody; phospholipase C; phosphorylation; tissue /cell culture

Central to immune responses is the activation, clonal expansion and differentiation of lymphocytes that carry receptors specific for the immunizing antigen. Upon antigen binding by receptor immunoglobulin (mIgM and mIgD) on B lymphocytes, signals are generated and transduced across the cell membrane which lead to rapid plasma membrane depolarization coupled to a subsequent increase in expression of membrane Ia antigens. Recent evidence suggests that sequential increased phosphatidylinositol (PI) hydrolysis and protein kinase C activation may be coupling events between receptor occupancy and membrane depolarization. We propose here to further examine the role of these events in mIg mediated signal transduction and to define possible mechanisms by which receptor crosslinking may lead to increased phospholipid turnover. In view of evidence that receptor mIgM and mIgD expressed on the same cell may function differently, we will also define and compare effects of independent crosslinking of these receptors on phospholipid metabolism and protein phosphorylation. Specifically, we propose to define and compare the effects of fragments of control antibodies and antibodies specific for mouse Fab, IgM and IgD on B cell phospholipid metabolism and protein phosphorylation. We will determine the effects of receptor immunoglobulin crosslinking on cellular phospholipase C activity and localization, and on phospholipid compartmentalization within the cell membrane. If phospholipid recompartmentalization is observed, we will determine, using a reconstituted liposome system, if this phenomenon is responsible for increased phosphotidylinositol hydrolysis by phospholipase C. Results will contribute significantly to our understanding of the mechanism of mIg mediated transmembrane signaling.

免疫应答的中心是激活、克隆扩增和免疫应答。 淋巴细胞的分化，这些淋巴细胞携带特异性的受体， 免疫抗原 通过受体免疫球蛋白（mIgM）结合抗原后 和mIgD），信号产生并通过 细胞膜，导致快速质膜去极化耦合到 膜Ia抗原的表达随后增加。 最近 有证据表明，连续增加磷脂酰肌醇（PI） 水解和蛋白激酶C活化可能是 受体占有率和膜去极化。 我们在此建议， 检查这些事件在mIg介导的信号转导中的作用， 定义受体交联可能导致 增加磷脂周转。 鉴于mIgM受体 在同一细胞上表达的mIgD可能有不同的功能，我们还将 定义并比较这些受体的独立交联效应 对磷脂代谢和蛋白质磷酸化的影响。 我们特别 建议定义和比较控制片段的效果 抗体和对B细胞上的小鼠Fab、IgM和IgD特异的抗体 磷脂代谢和蛋白质磷酸化。 康贝特人将以 受体免疫球蛋白交联对细胞磷脂酶C的影响 活性和定位，并对磷脂区室化内 细胞膜。 如果观察到磷脂重新区室化， 将使用重组脂质体系统确定这种现象是否 负责增加磷脂酰肌醇水解， 脂酶C已 结果将大大有助于我们 了解mIg介导的跨膜信号传导机制。