The Astrocyte Nexus: Cx43 Protein Interactions

 描述（由申请人提供）：间隙连接介导的细胞间离子和代谢偶联在整个脑中的星形胶质细胞中提供稳态和信号传导功能，CNS病理学导致星形胶质细胞间隙连接信号传导的破坏并由星形胶质细胞间隙连接信号传导的破坏引起。现在众所周知，间隙连接蛋白（连接蛋白）与其他蛋白质相互作用，形成一个分子复合物，我们称之为“Nexus”。最近的数据表明，Nexus是一个高度动态的信号单元，其中连接蛋白与适配器和支架分子的直接连接与细胞骨架，细胞质和其他膜蛋白结合，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这种末端复合体的组织，从而控制血脑屏障的完整性。为了实现这一目标，我们建议：目的1：测试的假设，即本地化和流动性的间隙连接蛋白和它们的结合伙伴决定组织的星形胶质细胞endfeet。目标2.确定连接蛋白对内皮紧密连接形成的下游作用。目标3：假设本地化和移动性 我们相信，这些跨学科和创新的研究将为星形胶质细胞Nexus在细胞极性建立中的作用提供第一个分子见解，从而确定可以靶向的重要星形胶质细胞功能。 来逆转星形胶质细胞极性的紊乱

 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.