Pannexin Channels In Vascular Physiology & Inflammation

描述(由申请人提供)： 组织环境中细胞间的通讯对于许多生理过程是非常重要的。在健康的活细胞中，传导离子和其他分子穿过质膜的通道和跨膜转运体也与心血管和呼吸系统的病理有关。细胞外核苷酸(如三磷酸腺苷)及其衍生物影响血管生理的许多方面，如血管收缩和血压调节，以及疾病状态，如代谢综合征。最近一系列令人兴奋的观察表明，PAnnexin蛋白在质膜上形成通道，通过以非常受调节的方式渗透离子和/或核苷酸的释放，这些PAnnexin通道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。在一组独立和相互关联的观察中，pAnnexin通道还在从早期凋亡细胞释放核苷酸方面发挥作用，这些核苷酸似乎对与吞噬细胞沟通至关重要，进而促进迅速清除身体。由于死亡细胞的清除失败与动脉粥样硬化和呼吸道炎症有关，因此PAnnexin通道可能也在调节组织内的炎症方面发挥作用。通过这一P01应用验证的中心假设是，PAnnexin通道处于心血管系统内的正常内稳态和导致炎症、动脉粥样硬化和高血压的疾病状态之间的关键过渡期。组成这项提案的四个项目涉及PAnnexin通道的作用如下。项目1(Ravichandran)解决了PAnnexin通道在动脉粥样硬化、胆固醇外流和组织炎症过程中的细胞死亡和单核细胞募集中的作用；项目2(Isakson)解决了PAnnexin通道如何促进阻力血管中的血管收缩以调节血压，以及这种作用在肥胖中如何改变；项目3(Leitinger)解决了PAnnexin通道如何调节脂肪细胞的功能以及在肥胖、胰岛素抵抗和高血压中死亡的脂肪细胞所诱导的炎症；项目4(Bayliss)解决了生理状态和疾病状态下PAnnexin通道激活的分子机制。通过小鼠模型和体外研究的结合，以及机制方法的结合，以及能够改变Panx1功能的新化合物的初步鉴定，我们有望为血管生理学和高血压中的pAnnexin通道和嘌呤能信号提供令人兴奋的新见解，并为针对特定疾病状态下调节这些通道的开放和关闭的新的治疗策略提供基础。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.