Pannexin Channels In Vascular Physiology & Inflammation

总体项目摘要 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，以及其他代谢产物 严重影响血管生理学的许多方面，如交感神经诱导的血管收缩， 血压调节，以及疾病状态，如饮食诱导的心脏代谢综合征。最近 一系列令人兴奋的观察结果表明，泛连接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/或释放核苷酸，这些泛连接蛋白通道允许 细胞与其他细胞沟通。与此相一致的是，泛连接蛋白通道的表达改变已经被证实是一种重要的生物学机制。 与心血管和代谢紊乱有关独立地，泛连接蛋白通道也在以下方面发挥作用： 从早期凋亡细胞中释放核苷酸，这些核苷酸对于与吞噬细胞通讯至关重要， 和组织微环境。通过该PO 1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内稳态和心血管系统内的正常内稳态之间的关键中间相。 导致炎症和高血压的疾病状态。构成本提案的四个项目涉及 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 凋亡细胞：吞噬细胞之间的通讯，垂死的细胞和附近的调节抗- 炎症信号传导和调节组织炎症;项目2（Isakson）解决了泛连接蛋白如何 血管平滑肌细胞中的通道有助于阻力血管中的血管收缩以调节血液 压力，以及Pannexin 1如何将交感神经系统与动脉功能联系起来;项目3（Leitinger） 解决了泛连接蛋白通道如何调节炎症和肝纤维化的一部分， 心脏代谢综合征;项目4（Bayliss）阐述了泛连接蛋白通道激活的分子机制 在生理和疾病状态下。结合小鼠模型和离体研究， 机制的方法，并确定新的化合物能够改变Panx 1的功能，我们希望 为血管生理学中的泛连接蛋白通道和嘌呤能信号传导提供令人兴奋的新见解， 高血压，以及新的治疗策略的基础，目标是调节这些开放和关闭 特定疾病状态下的通道。我们希望我们的研究对心血管，代谢， 和呼吸道疾病。

OVERALL 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 derivatives, as well as other metabolites critically influence many aspects of vasculary physiology such as sympthetic nerve-induced vasoconstriction and blood pressure regulation, as well disease states such as diet-induced cardiometabolic 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. Independently, the pannexin channels also play a role in releasing nucleotides from early stage apoptotic cells that appear critical for communicating with phagocytes, and with the tissue microenvironment. The central hypothesis tested via this PO1 application is that pannexin channels sit at a critical interphase between normal homeostasis within the cardiovascular system, and the disease states leading inflammation, 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 apoptotic cell:phagocyte communication, between dying cells and the neighborhood in regulating anti- inflammatory signaling, and regulating tissue inflammation; Project 2 (Isakson) addresses how pannexin channels in vascular smooth muscle cells contribute to vasoconstriction in resistance vessels to regulate blood pressure, and how Pannexin 1 links sympathetic nervous system to arterial function; Project 3 (Leitinger) addresses how pannexin channels regulate inflammation and fibrosis of the liver as part of the larger cardiometabolic syndrome; 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 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 the basis for novel treatment strategies targeting the regulated opening and closing of these channels in specific disease states. We expect our studies have a broad impact to cardiovascular, metabolic, and and respiratory diseases.