The Astrocyte Nexus: Cx43 Protein Interactions

 描述(申请人提供)：缝隙连接介导的细胞间离子和代谢偶联在整个大脑中的星形胶质细胞之间提供动态平衡和信号传递功能，中枢神经系统病理导致并由星形胶质细胞缝隙连接信号中断引起。现在众所周知，缝隙连接蛋白(间隙连接蛋白)与其他蛋白质相互作用，形成一种我们称之为“Nexus”的分子复合体。最近的数据表明，Nexus是一个高度动态的信号单位，连接蛋白与接头和支架分子的直接连接结合到细胞骨架、细胞质和其他膜蛋白上，使星形胶质细胞极化。这项拨款提案的总体目标是了解星形胶质细胞中的缝隙连接如何控制端足复合体的组织，从而控制血脑屏障的完整性。为了实现这一目标，我们建议：目标1：检验缝隙连接蛋白及其结合伙伴的定位和移动性决定星形胶质细胞端足组织的假设。目的2.确定连接蛋白在内皮紧密连接形成中的下游作用。目标3.验证本地化和流动性的假设 缝隙连接蛋白及其结合伙伴的变化决定了利用表达连接蛋白修饰的小鼠星形胶质细胞端脚的组织。我们相信，这些跨学科和创新性的研究将为星形胶质细胞Nexus I建立细胞极性的作用提供第一个分子洞察力，从而确定可以靶向的重要星形胶质细胞功能 逆转星形胶质细胞的极性紊乱。

 DESCRIPTION (provided by applicant): Gap junction-mediated intercellular ionic and metabolic coupling provides both homeostatic and signaling functions among astrocytes throughout the brain, and CNS pathology both results in and is caused by disruptions in astrocyte gap junction signaling. It is now well known that gap junction proteins (connexins) interact with other proteins, forming a molecular complex we term the "Nexus". Recent data indicate that Nexus is a highly dynamic signaling unit, where direct linkages of connexins to adaptor and scaffolding molecules are bound to cytoskeletal, cytoplasmic and other membrane proteins, polarizing the astrocyte. The overall goal of this grant proposal is to understand how gap junctions in astrocytes control organization of this endfoot complex and thus control blood-brain-barrier integrity. To accomplish this goal, we propose to: Aim 1: Test the hypothesis that localization and mobility of gap junction proteins and their binding partners determines organization of astrocyte endfeet. Aim 2. Determine downstream effects of connexins on endothelial tight junction formation. Aim 3. Validate the hypothesis that localization and mobility of gap junction proteins and their binding partners determines organization of astrocyte endfeet using mice with modified connexin expression We believe that these interdisciplinary and innovative studies will provide the first molecular insights into the role of the astrocyte Nexus i establishment of cell polarity and thus identify important astrocyte functions that can be targeted to reverse disorders of astrocyte polarity.