Bimp3 in Antigen Receptor Signaling and MALT Lymphoma

Bimp3 在抗原受体信号转导和 MALT 淋巴瘤中的作用

• 批准号: 6556070
• 负责人: LINDA M MCALLISTER-LUCAS
• 金额: $ 13.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-25 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556070
• 关键词: B cell receptor; B lymphocyte; BCL2 gene /protein; SDS polyacrylamide gel electrophoresis; T cell receptor; antigen receptors; biological signal transduction; gel mobility shift assay; genetically modified animals; guanosine monophosphate; immunoprecipitation; laboratory mouse; leukocyte activation /transformation; lymphoma; membrane proteins; neoplastic transformation; nuclear factor kappa beta; protein kinase; protein protein interaction; protein structure function; receptor expression; secretory immune system; tissue support frame

DESCRIPTION (provided by applicant): The Bimps (BcI10 Interacting MAGUK Proteins) are a newly described family of signaling proteins that activate the pro-survival transcription factor, NF-kappaB. Bimps belong to the larger MAGUK (Membrane Associated Guanylate Kinase) family, a class of proteins composed of multiple distinct protein/protein interaction domains that function as molecular scaffolds in assembling multiprotein complexes at the plasma membrane. Bimps bind to and operate upstream of Bcl10, an NF-kappaB signaling molecule that is known to be an essential mediator of lymphocyte proliferation in response to antigen. The genes encoding Bcl10 and its downstream binding partner, MALT1, are each targets of recurrent chromosomal translocation in mucosa associated lymphoid tissue (MALT) lymphoma, suggesting that perturbation of the Bcl10-mediated NF-kappaB signaling pathway can promote lymphomatous transformation. Our preliminary data suggest that the Bimp proteins function to link surface receptor signaling and subsequent protein kinase C (PKC) activation to Bcl10-mediated induction of NF-(B. We hypothesize that the lymphocyte specific Bimp isoform, Bimp3, functions as a scaffold to assemble the signaling molecules that are required for Bcl10/MALT1-mediated NF-(B activation in response to lymphocyte antigen receptor stimulation. Furthermore, we hypothesize that disruption of the normal mechanisms by which the antigen receptor and Bimp3 regulate Bcl10 and MALT1 activity, as a consequence of chromosomal translocation, contributes to the pathogenesis of MALT lymphoma. In order to test these hypotheses, we propose three specific aims: 1) Determine if Bimp3, Bcl10 and MALT1 participate in a common NF-(B signaling pathway in lymphocytes with known antigen receptor-related signaling molecules; 2) Delineate the function of the individual protein/protein interaction domains within the Bimp3 structure, and 3) Characterize the physiological role of Bimp3 by generating and analyzing mice deficient in Bimp3. The career development program outlined in this proposal will build upon the investigator's prior research experience and will also provide the opportunity to master new laboratory techniques, to interact with a new mentor and team of collaborators, and to participate in additional didactic training in immunology, mouse genetics and bioinformatics. This training experience will ultimately lead to transition to the status of independent investigator.

描述(申请人提供)：BIMPS(BcI10相互作用的Maguk蛋白)是一个新描述的信号蛋白家族，激活促进生存的转录因子NF-kappaB。BIMP属于较大的MAGUK(膜相关鸟苷酸激酶)家族，是一类由多个不同的蛋白质/蛋白质相互作用结构域组成的蛋白质，其功能是在质膜上组装多蛋白复合体的分子支架。BIMP结合并作用于Bcl10的上游，Bcl10是一种核因子-kappaB信号分子，被认为是抗原反应中淋巴细胞增殖的重要中介。在黏膜相关淋巴组织(MALT)淋巴瘤中，编码Bcl10及其下游结合伙伴MALT1的基因都是反复发生的染色体易位的靶点，提示Bcl10介导的NF-kappaB信号通路的干扰可以促进淋巴瘤的转化。 我们的初步数据表明，Bimp蛋白的功能是将表面受体信号和随后的蛋白激酶C(PKC)激活与Bcl10介导的NF-(B)诱导联系起来。我们假设淋巴细胞特有的Bimp亚型Bimp3作为支架，组装Bcl10/MALT1介导的NF-B激活所需的信号分子，以响应淋巴细胞抗原受体的刺激。此外，我们假设，作为染色体易位的结果，抗原受体和Bimp3调节Bcl10和MALT1活性的正常机制的破坏有助于MALT淋巴瘤的发病。为了验证这些假设，我们提出了三个具体目标：1)确定Bimp3、Bcl10和MALT1是否参与已知抗原受体相关信号分子的淋巴细胞中共同的核因子(B)信号通路；2)描述Bimp3结构中各个蛋白质/蛋白质相互作用区域的功能；以及3)通过建立和分析Bimp3缺陷小鼠来表征Bimp3的生理作用。本提案中概述的职业发展计划将建立在研究人员以前的研究经验的基础上，还将提供掌握新的实验室技术、与新的导师和合作者团队互动的机会，以及参加免疫学、小鼠遗传学和生物信息学的额外教学培训。这一培训经历最终将导致过渡到独立调查员的地位。