Pannexin Channels In Vascular Physiology & Inflammation

描述（由申请人提供）： 组织环境内细胞之间的细胞间通讯对于许多生理过程是至关重要的。在健康活细胞中传导离子和其他分子穿过质膜的通道和跨膜转运蛋白也与心血管和呼吸系统的病理有关。细胞外核苷酸（如ATP）及其衍生物严重影响血管生理学的许多方面，如血管收缩和血压调节，以及疾病状态，如代谢综合征。最近令人兴奋的一系列观察表明，泛连接蛋白蛋白在质膜上形成通道，并且通过以非常受调节的方式渗透离子和/或释放核苷酸，这些泛连接蛋白通道允许细胞与其他细胞通信。与此一致，泛连接蛋白通道的表达改变与心血管和代谢紊乱有关。在一组独立和相互关联的观察结果中，泛连接蛋白通道还在从早期凋亡细胞释放核苷酸中发挥作用，所述早期凋亡细胞对于与吞噬细胞通信似乎是关键的，并且反过来促进迅速的尸体去除。由于死亡细胞的清除失败与动脉粥样硬化和气道炎症有关，因此泛连接蛋白通道可能也在调节组织内的炎症中发挥作用。通过该P01应用测试的中心假设是，泛连接蛋白通道位于心血管系统内的正常稳态与导致炎症、动脉粥样硬化和高血压的疾病状态之间的关键间期。组成该提案的四个项目解决了泛连接蛋白通道的作用，如下所示。项目1项目2（Isakson）阐述了平滑肌细胞中的泛连接蛋白通道如何促进阻力血管中的血管收缩以调节血压，以及这在肥胖症中如何改变;项目3（Leitinger）阐述了泛连接蛋白通道如何调节脂肪细胞功能以及肥胖、胰岛素抵抗和高血压中死亡脂肪细胞诱导的炎症;项目4（Bayliss）解决了生理和疾病状态下泛连接蛋白通道激活的分子机制。结合小鼠模型和离体研究，和机制的方法，以及能够改变Panx1功能的新化合物的初步鉴定，我们希望提供令人兴奋的新见解泛连接蛋白通道和嘌呤能信号在血管生理学和高血压，并提供新的治疗策略的基础上，针对这些通道在特定的疾病状态调节开放和关闭。我们预计这将对心血管、代谢和呼吸系统疾病产生广泛影响。

DESCRIPTION (Provided by applicant): 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 nucleotides (such as ATP) and their derivatives 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 cardiovascular 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.