Bimp3 in Antigen Receptor Signaling and MALT Lymphoma

描述（由申请人提供）： Bimps（BcI 10 Interacting MAGUK Proteins）是一个新发现的信号蛋白家族，它激活促生存转录因子NF-κ B。 Bimps属于较大的MAGUK（膜相关鸟苷酸激酶）家族，这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，其在质膜上组装多蛋白质复合物时充当分子支架。 Bimps结合并在Bcl 10的上游操作，Bcl 10是一种NF-κ B信号传导分子，已知其是淋巴细胞应答抗原增殖的重要介质。 编码Bcl 10及其下游结合伴侣MALT 1的基因是粘膜相关淋巴组织（MALT）淋巴瘤中复发性染色体易位的靶基因，这表明Bcl 10介导的NF-κ B信号通路的扰动可以促进淋巴瘤转化。 我们的初步数据表明，Bimp蛋白的功能是将表面受体信号传导和随后的蛋白激酶C（PKC）激活与Bcl 10介导的NF-（B）诱导联系起来。 我们假设，淋巴细胞特异性Bimp亚型，Bimp 3，作为一个支架组装信号分子，需要Bcl 10/MALT 1介导的NF-β B激活淋巴细胞抗原受体刺激。 此外，我们推测，破坏正常机制，抗原受体和BIMP 3调节Bcl 10和MALT 1活性，作为染色体易位的结果，有助于MALT淋巴瘤的发病机制。 为了检验这些假设，我们提出了三个具体目标：1）确定Bimp 3、Bcl 10和MALT 1是否参与共同的NF-κ B，（B信号通路在淋巴细胞与已知的抗原受体相关的信号分子; 2）描述Bimp 3结构内的单个蛋白质/蛋白质相互作用结构域的功能，和3）通过产生和分析缺陷于Bimp 3的小鼠来表征Bimp 3的生理作用。 本提案中概述的职业发展计划将建立在研究者先前的研究经验基础上，并将提供掌握新实验室技术的机会，与新的导师和合作者团队互动，并参加免疫学，小鼠遗传学和生物信息学的额外教学培训。 这一培训经验将最终导致过渡到独立调查员的地位。

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.