Pannexin Channels In Vascular Physiology & Inflammation

整体项目总结 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。胞外核素(如三磷酸腺苷)及其衍生物以及其他代谢物 严重影响血管生理学的许多方面，如症状性神经诱导的血管收缩和 血压调节，以及饮食引起的心脏代谢综合征等疾病状态。近期 一系列令人兴奋的观察表明，PAnnexin蛋白在质膜上形成通道，并且 通过以一种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通信。与此一致，pAnnexin通道的表达发生了变化 与心脏血管和代谢紊乱有关。独立地，pAnnexin通道也在 从早期的凋亡细胞中释放核苷酸，这些核苷酸似乎对与吞噬细胞的通讯至关重要， 与组织微环境的关系。通过PO1应用程序检验的中心假设是pAnnexin 通道处于心血管系统内正常内稳态和 疾病状态导致炎症和高血压。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 凋亡细胞：死亡细胞与邻近细胞之间的吞噬细胞通讯，调节抗 炎症信号和调节组织炎症；项目2(Isakson)解决了PAnnexin如何 血管平滑肌细胞中的通道参与阻力血管的收缩以调节血液 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) 阐述了PAnnexin通道如何调节肝脏的炎症和纤维化 心脏代谢综合征；项目4(Bayliss)阐述了pAnnexin通道激活的分子机制 处于生理和疾病状态。结合小鼠模型和体外研究，以及 机械方法，以及鉴定能够改变Panx1功能的新化合物，我们希望 为血管生理学和生物学中的pAnnexin通道和嘌呤能信号提供令人振奋的新见解 高血压，以及针对这些调节的开放和关闭的新的治疗策略的基础 处于特定疾病状态的经络。我们预计我们的研究将对心血管、新陈代谢、 以及呼吸系统疾病。

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.