Mouse Support Core

总体方案项目-项目摘要 组织环境内的细胞之间的细胞间通信对于许多人来说是根本重要的。 生理过程。传导离子和其他分子的通道和跨膜转运蛋白 在健康的活细胞中，跨质膜的蛋白质也与心血管疾病有关， 呼吸系统细胞外核苷酸（如ATP）及其衍生物严重影响许多 血管生理学方面，如血管收缩和血压调节，以及疾病状态 例如代谢综合征。最近令人兴奋的一系列观察表明，泛连接蛋白的形成 细胞膜上的通道，并通过渗透离子和/或核苷酸的释放，在一个非常 这些泛连接蛋白通道允许细胞与其他细胞进行通信。与此相一致， 泛连接蛋白通道表达的改变与心血管和代谢紊乱有关。上 独立和相互关联的一组观察结果，泛连接蛋白通道也在释放 来自早期凋亡细胞的核苷酸，其对于与吞噬细胞的通讯至关重要， 迅速转移尸体因为，死亡细胞的清除失败与动脉粥样硬化和气道 在炎症中，泛连接蛋白通道可能也在调节组织内的炎症中起作用。中央 通过该P01应用测试的假设是，泛连接蛋白通道位于正常 心血管系统内的稳态，以及导致炎症，动脉粥样硬化， 和高血压。组成该提案的四个项目解决了泛连接蛋白通道的作用， 如下项目1（Ravichandran）解决了泛连接蛋白通道在细胞死亡和细胞增殖中的作用。 动脉粥样硬化、胆固醇流出和组织炎症中的单核细胞;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的血管收缩 调节血压以及肥胖如何改变血压;项目3（Leitinger）讨论了泛连接蛋白如何改变血压 通道调节脂肪细胞功能和肥胖症中死亡脂肪细胞诱导的炎症，胰岛素 阻力和高血压;项目4（Bayliss）解决泛连接蛋白通道的分子机制 在生理和疾病状态下激活。结合小鼠模型和离体研究， 和机制的方法，以及能够改变Panx 1的新化合物的初步鉴定 功能，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，并为针对受调节的 这些通道在特定疾病状态下的打开和关闭。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.