The actin cytoskeleton in Beta cell activation

描述（由申请方提供）：严格调节B细胞活化，以确保抗体应答的特异性和有效性。这种调节的异常导致免疫缺陷和自身免疫性疾病。相反，疫苗的效力取决于其激活B细胞应答的能力。本项目的长期目标是阐明启动和调节B细胞活化的细胞和分子机制。B细胞活化通过抗原与B细胞抗原受体（BCR）的结合而启动，其诱导信号传导级联和抗原内化以用于加工和呈递。BCR的独特之处在于它识别天然形式的抗原，并作为信号转导和抗原转运蛋白。BCR协调其两个功能以实现最佳激活水平。B细胞活化的早期事件是BCR与肌动蛋白细胞骨架和肌动蛋白细胞骨架重组的关联。最近的研究表明，肌动蛋白细胞骨架是BCR介导的抗原转运所必需的，并参与调节BCR信号传导。然而，肌动蛋白细胞骨架调节BCR功能的潜在机制尚未得到很好的研究。哺乳动物肌动蛋白结合蛋白1（mAbp 1/SH 3 P7/HP-55）是一种能同时与F-肌动蛋白和其他细胞系统蛋白相互作用的蛋白质，是连接肌动蛋白细胞骨架和BCR之间相互作用的潜在接头。该提议的中心假设是，在对不同抗原的应答中，BCR差异性地激活mAbp 1并诱导mAbp 1与BCR信号传导和抗原转运机构的相互作用，其将肌动蛋白细胞骨架与BCR信号传导和抗原转运机构连接起来。为了验证这一假设，我们建议确定mAbp 1在BCR的信号传导和抗原转运功能中的作用，检查BCR触发的mAbp 1的激活，并分析mAbp 1与BCR信号传导和抗原转运途径的组分的相互作用。拟议的研究结合联合收割机遗传学，细胞生物学和生物化学的方法，旨在确定新的功能mAbp 1在B细胞活化和描绘的BCR和肌动蛋白细胞骨架之间的功能相互作用的分子基础。这些研究将增加我们对调节B细胞活化的潜在机制的理解，并增强我们操纵和控制抗体应答的能力。

DESCRIPTION (provided by applicant): B cell activation is tightly regulated to ensure the specificity and efficacy of the antibody responses. Abnormalities in this regulation lead to immune deficiency and autoimmune diseases. Conversely, the efficacy of a vaccine depends on its ability to activate B cell responses. The long term goal, of this project is to delineate the cellular and molecular mechanism for the initiation and regulation of B cell activation. B cell activation is initiated by the binding of antigens to the B cell antigen receptor (BCR), which induces signaling cascades and antigen internalization for processing and presentation. The BCR is unique in that it recognizes antigens in their native forms and serves as a signaling transducer as well as an antigen transporter. The BCR coordinates its two functions to achieve an optimal level of activation. An early event in B cell activation is the association of the BCR with the actin cytoskeleton and the actin cytoskeleton reorganization. Recent studies show that the actin cytoskeleton is required for BCR-mediated antigen transport and is involved in regulating BCR signaling. However, the underlying mechanism by which the actin cytoskeleton regulates BCR functions has not been well studied. Mammalian actin-binding protein 1 (mAbp1/SH3P7/HP-55) that has been shown to simultaneously interact with F-actin and proteins of the other cellular systems is one of the potential linkers that bridge the interaction between the actin cytoskeleton and the BCR. The central hypothesis of this proposal is that in response to different antigens, the BCR differentially activates the mAbp1 and induces the interaction of mAbp1 with BCR signaling and antigen- transport machineries, which links the actin cytoskeleton with BCR signaling and antigen-transport apparatus. To test this hypothesis, we propose to define the roles of mAbp1 in the signaling and antigen- transport functions of the BCR, to examine BCR-triggered activation of mAbp1, and to analyze the interaction of mAbp1 with the components of BCR signaling and antigen-transport pathways. The proposed studies combine genetic, cell biological, and biochemical approaches and aim to identify novel functions of mAbp1 in B cell activation and delineate the molecular basis for the functional interaction between the BCR and the actin cytoskeleton. These studies will increase our understanding of underlying mechanisms for regulation of B cell activation and enhance our ability to manipulate and control antibody responses.