Role of Pannexins in Vascular Smooth Muscle Cells

总体计划项目--项目摘要 组织环境中细胞之间的细胞间通信对许多人来说是非常重要的 生理过程。传导离子和其他分子的通道和跨膜转运体 在健康的活细胞中穿过质膜也与心血管和 呼吸系统。细胞外核素(如三磷酸腺苷)及其衍生物对许多 血管生理学方面，如血管收缩和血压调节，以及疾病状态 比如代谢综合征。最近一系列令人兴奋的观察表明，pAnnexin蛋白形成 质膜上的通道，并通过渗透离子和/或释放核苷酸在非常 这些pAnnexin通道以受调控的方式允许细胞与其他细胞进行交流。与此一致的是， PAnnexin通道表达的改变与心血管和代谢紊乱有关。在An上 独立和相互关联的一组观察结果，pAnnexin通道也在释放 来自早期凋亡细胞的核苷酸，它们似乎对与吞噬细胞的通讯至关重要，进而 促进迅速移走身体。因为，死亡细胞清除失败与动脉粥样硬化和呼吸道有关。 炎症，Pannexin通道可能也在调节组织内的炎症方面发挥作用。中环 通过这一P01应用验证的假设是，pAnnexin通道位于正常 心血管系统内的动态平衡，疾病状态导致炎症，动脉粥样硬化， 还有高血压。组成这项提案的四个项目涉及PAnnexin通道的作用，如 下面是。项目1(Ravichandran)阐述了pAnnexin通道在细胞死亡和招募过程中的作用 单核细胞在动脉粥样硬化、胆固醇外流和组织炎症中的作用；项目2(Isakson) 探讨平滑肌细胞膜联蛋白通道在阻力血管收缩中的作用 调节血压以及肥胖患者血压如何改变；项目3(Leitinger)解决了膜联蛋白是如何 通道调节肥胖脂肪细胞功能和死亡脂肪细胞引起的炎症，胰岛素 耐药与高血压；项目4(Bayliss)阐述了pAnnexin通道的分子机制 生理状态和疾病状态下的激活。通过小鼠模型和体外研究相结合， 和机械方法，以及能够改变Panx1的新化合物的初步鉴定 功能，我们期望对血管内膜联蛋白通道和嘌呤能信号提供令人兴奋的新见解。 生理学和高血压，并为针对受调控者的新治疗策略提供基础 在特定疾病状态下打开和关闭这些通道。我们预计这将产生广泛的影响 心血管、代谢和呼吸系统疾病。

Overall Program Project - Project Summary Inter-cellular communication between cells within a tissue environment is fundamentally important for many physiological processes. Channels and transmembrane transporters that conduct ions and other molecules across the plasma membrane in healthy living cells are also linked to pathologies of the cardiovascular and respiratory systems. Extracellular nucleltides (such as ATP) and their derivatires critically influence many aspects of vascular physiology such as vasoconstriction and blood pressure regulation, as well disease states such as metabolic syndromes. Recent exciting series of observations suggest that the pannexin proteins form channels on the plasma membrane, and by permeating ions and/or the release of nucleotides in a very regulated manner, these pannexin channels allow cells to communicate with other cells. Consistent with this, altered expression of pannexin channels have been linked to cardovascular and metabolic disorders. On an independent and inter-related set of observations, the pannexin channels also play a role in releasing nucleotides from early stage apoptotic cells that appear critical for communicating with phagocytes and in turn promoting prompt corpse removal. Since, failed clearance of dying cells is linked to atherosclerosis and airway inflammation, pannexin channels likely also play a role in regulating inflammation within tissues. The central hypothesis tested via this P01 application is that pannexin channels sit at a critical interphase between normal homeostasis within the cardiovascular system, and the disease states leading inflammation, atherosclerosis, and hypertension. The four projects that comprise this proposal address the role of pannexin channels as follows. Project 1 (Ravichandran) addresses the role of pannexin channels in cell death and recruitment of monocytes during atherosclerosis, cholesterol efflux, and in tissue inflammation; Project 2 (Isakson) addresses how pannexin channels in smooth muscle cells contribute to vasoconstriction in resistance vessels to regulate blood pressure and how this is altered in obesity; Project 3 (Leitinger) addresses how pannexin channels regulate adipocyte functions and the inflammation induced by dying adipocytes in obesity, insulin resistance and hypertension; Project 4 (Bayliss) addresses molecular mechanisms of pannexin channel activation in physiological and diseased states. With the combination of mouse models and ex vivo studies, and mechanistic approaches, and the preliminary identification of new compounds capable of altering Panx1 function, we expect to provide exciting new insights on pannexin channels and purinergic signaling in vascular physiology and hypertension, and provide the basis for novel treatment strategies targeting the regulated opening and closing of these channels in specific disease states. We expect this would have a broad impact to cardiovascular, metabolic, and respiratory diseases.