CD81 AND B CELL ANTIGEN RECEPTOR SIGNALING

CD81 和 B 细胞抗原受体信号转导

• 批准号: 2856077
• 负责人: Erdyni Nikolaevich Tsitsikov
• 金额: $ 11.52万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856077
• 关键词: B cell receptor; B lymphocyte; CD antigens; antigen receptors; biological signal transduction; calcium flux; crosslink; electroporation; enzyme activity; flow cytometry; genetically modified animals; immunoglobulin M; immunoprecipitation; laboratory mouse; lymphocyte proliferation; membrane proteins; phosphorylation; protein structure function; protein tyrosine phosphatase; receptor sensitivity; surface antigens; western blottings

DESCRIPTION (Adapted from the Investigator's Abstract): The purpose of this project is to analyze the role of CD81, a component of the complement receptor 2 (CR2) complex, along with CD21, CD19 and Leu13, in signaling via the B cell antigen receptor (BCR). Co-ligation of the CR2 complex with the BCR amplifies signal transduction through the BCR. In an effort to understand the role of CD81 in B cell development and function, the investigator has generated mice with the CD81 gene disrupted. Preliminary analysis of these mice reveals grossly normal T and B cell development except for a large decrease in the number of B1 cells. CD81-/- mice expressed markedly decreased amounts of CD19 on their B cells, yet they had increased serum IgM and IgA, exhibited an exaggerated antibody response to the type II T-independent antigen TNP-Ficoll, and produced anti-DNA antibodies. These results suggest that B cells from CD81-deficient mice are hyperresponsive to signaling via the BCR. Dr. Tsitsikov proposes to investigate this hyperresponsiveness and to delineate residues in CD81 that are important for its function in modulating BCR signaling. The specific aims are: 1) to perform a detailed analysis of BCR signaling in CD81-deficient B cells, including examination of B cell proliferation, protein tyrosine phosphorylation, and calcium fluxes following crosslinking of membrane IgM, 2) to analyze the functional and physical interactions of the BCR and its co-receptors, CD19 and CD22 and phosphatases, and 3) to perform a mutational analysis of CD81 function in a murine B cell line and in transgenic mice expressing mutant forms of CD81. The proposed studies of the role of CD81 in BCR signaling may have important implications for the understanding and treatment of autoimmune diseases.

描述（改编自研究者摘要）：本研究的目的 项目是分析CD 81的作用，CD 81是补体的一个组成部分， 受体2（CR2）复合物，沿着与CD 21、CD 19和Leu 13一起，通过 B细胞抗原受体（BCR）。 将CR2复合物与 BCR通过BCR放大信号转导。 为了努力 了解CD 81在B细胞发育和功能中的作用， 研究人员已经产生了CD 81基因被破坏的小鼠。 初步 对这些小鼠的分析显示T和B细胞发育大体正常 除了B1细胞数量的大量减少。 CD 81-/-小鼠 在他们的B细胞上表达的CD 19数量明显减少，但他们 血清IgM和伊加增加，表现出夸大的抗体反应， II型T-非依赖性抗原TNP-Ficoll，并产生抗DNA 抗体的 这些结果表明，来自CD 81缺陷小鼠的B细胞是 对通过BCR的信号反应过度。 Tsitsikov博士建议 研究这种高反应性并描绘CD 81中 对于其调节BCR信号传导的功能是重要的。 具体 目的是：1）对BCR信号进行详细分析， CD 81缺陷型B细胞，包括检查B细胞增殖， 蛋白质酪氨酸磷酸化和交联后的钙通量 2）分析膜IgM的功能和物理相互作用， BCR及其共受体，CD 19和CD 22以及磷酸酶，以及3） 在鼠B细胞系中进行CD 81功能的突变分析， 在表达突变形式的CD 81的转基因小鼠中。 拟议的研究 CD 81在BCR信号传导中的作用可能对BCR的发生有重要意义。 了解和治疗自身免疫性疾病。