REGULATION OF B-CELL FUNCTION BY SRC TYROSINE KINASES

SRC 酪氨酸激酶对 B 细胞功能的调节

基本信息

批准号：
3468976
负责人：
KRISTIN M ABRAHAM
金额：
$ 9.37万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-07-01 至 1998-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3468976
关键词：
B lymphocyte antibody formation antibody receptor biological signal transduction cell differentiation cell transformation enzyme activity gene expression genetic transduction genetically modified animals laboratory mouse leukopoiesis protein tyrosine kinase tissue /cell culture

项目摘要

Clonal expansion during an immune response reflects the selection of lymphocytes bearing antigen-reactive receptors from among a highly diverse population of available clones. Clonal selection operates via the B lymphocyte immunoglobulin receptor (IgR), which functions to provide the appropriate stimulation for cell growth and differentiation. The affinity of the IgR for antigen likely imposes the restriction on the response, such that only clones bearing receptors of appropriate affinity will expand, differentiate and secrete immunoglobulin. How the affinity of the IgR is subsequently translated into cellular activation (versus no activation) remains enigmatic. Among the earliest intracellular biochemical events observed following IgR stimulation is a rapid stimulation of protein tyrosine kinase activity. This proposal seeks support for an investigation of the potential role of src-family protein tyrosine kinases in these proximal IgR signalling responses. the proposed experiments will initially define the array of src-family protein tyrosine kinases expressed in developing B lymphocytes, and outline molecular aspects of their developmental regulation. A central feature of this proposal is the subsequent genetic manipulation of endogenous levels of protein tyrosine kinases in otherwise normal B lymphocytes using both in vitro and in vivo strategies. In this way, protein tyrosine kinase activity encoded by specific src-family kinases will be correlated with specific changes in lymphocyte maturation and IgR signalling. The relationship between src-family protein tyrosine kinase activity and clonal selection will subsequently be examined by monitoring the genotypic character of antibody populations produced from genetically manipulated cells during a highly defined antigen-specific response in vivo. These studies will substantially increase our understanding of src-protein tyrosine kinase-mediated regulation of B lymphopoiesis and oncogenesis, IgR signalling, and clonal selection.

免疫反应期间的克隆扩增反映了淋巴细胞带有抗原反应性受体，来自高度可用克隆的多样化群体。克隆选择通过以下方式进行 B 淋巴细胞免疫球蛋白受体 (IgR)，其功能是为细胞生长和分化提供适当的刺激。 IgR 对抗原的亲和力可能会限制反应，这样只有具有适当亲和力的受体的克隆会扩增、分化并分泌免疫球蛋白。亲和力如何 IgR 的随后被转化为细胞激活（相对于没有激活）仍然是个谜。最早的细胞内 IgR 刺激后观察到的生化事件是快速的刺激蛋白酪氨酸激酶活性。该提案寻求支持 src 家族蛋白潜在作用的研究这些近端 IgR 信号传导反应中的酪氨酸激酶。这提议的实验将首先定义 src-family 数组在发育中的 B 淋巴细胞中表达的蛋白酪氨酸激酶，以及概述其发育调节的分子方面。一个中央该提案的特点是随后的基因操纵正常 B 细胞中蛋白酪氨酸激酶的内源水平使用体外和体内策略的淋巴细胞。这样，由特定 src 家族激酶编码的蛋白酪氨酸激酶活性与淋巴细胞成熟度和 IgR 的特定变化相关发出信号。 src家族蛋白酪氨酸激酶之间的关系随后将通过监测来检查活性和克隆选择基因产生的抗体群体的基因型特征在高度定义的抗原特异性反应期间操纵细胞体内。这些研究将大大增加我们对 src-蛋白酪氨酸激酶介导的 B 淋巴细胞生成调节肿瘤发生、IgR 信号传导和克隆选择。