The actin cytoskeleton in Beta cell activation

Beta 细胞激活中的肌动蛋白细胞骨架

• 批准号: 7093288
• 负责人: WENXIA SONG
• 金额: $ 25.99万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093288
• 关键词: actins; antigens; cytoskeleton

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.

描述（由申请人提供）：B 细胞激活受到严格调控，以确保抗体反应的特异性和有效性。这种调节的异常会导致免疫缺陷和自身免疫性疾病。相反，疫苗的功效取决于其激活 B 细胞反应的能力。该项目的长期目标是描绘 B 细胞激活启动和调节的细胞和分子机制。 B 细胞激活是通过抗原与 B 细胞抗原受体 (BCR) 的结合来启动的，这会诱导信号级联和抗原内化以进行处理和呈递。 BCR 的独特之处在于它能够识别天然形式的抗原，并充当信号转导器和抗原转运蛋白。 BCR 协调其两个功能以实现最佳激活水平。 B 细胞激活的早期事件是 BCR 与肌动蛋白细胞骨架的结合以及肌动蛋白细胞骨架的重组。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充分研究。哺乳动物肌动蛋白结合蛋白 1 (mAbp1/SH3P7/HP-55) 已被证明可同时与 F-肌动蛋白和其他细胞系统的蛋白质相互作用，是桥接肌动蛋白细胞骨架和 BCR 之间相互作用的潜在接头之一。该提议的中心假设是，响应不同的抗原，BCR 差异性地激活 mAbp1 并诱导 mAbp1 与 BCR 信号传导和抗原转运机制相互作用，从而将肌动蛋白细胞骨架与 BCR 信号传导和抗原转运装置连接起来。为了检验这一假设，我们建议定义 mAbp1 在 BCR 信号传导和抗原转运功能中的作用，检查 BCR 触发的 mAbp1 激活，并分析 mAbp1 与 BCR 信号传导和抗原转运途径成分的相互作用。拟议的研究结合了遗传、细胞生物学和生化方法，旨在确定 mAbp1 在 B 细胞激活中的新功能，并描绘 BCR 和肌动蛋白细胞骨架之间功能相互作用的分子基础。这些研究将增加我们对 B 细胞激活调节的潜在机制的理解，并增强我们操纵和控制抗体反应的能力。