Ca2+ signaling Networks in Health and Disease

项目摘要 我们的研究整合了Ca 2+通道活性的基本生化和生物物理基础， 人类疾病的动物模型。我们寻求了解本地渠道是如何 构建，激活和调节，它们如何控制生理上的重要功能 系统以及它们的功能改变如何驱动疾病。我们专注于Ca 2+信号转导 蛋白质、奥赖、STIM、MCU和NCLX。奥赖通道由三个独立的基因编码 （Orai 1 -3）并被内质网（ER）Ca 2+感应蛋白STIM（STIM 1 - 3）激活。 2）。奥赖代表了一个高钙离子选择性通道家族，它位于人的质膜（PM）上， 几乎所有的细胞。作为该家族的创始成员，ORAI 1与STIM 1在生理上相互作用， ER-PM连接，以介导钙库操纵的钙内流（SOCE）。SOCE对于控制 几乎所有细胞都具有许多生理功能，包括分泌、迁移和增殖 类型然而，ORAI 2、ORAI 3和大肠杆菌特异性蛋白的生理作用是不确定的。 翻译变体ORAI 1称为ORAI 1 α仍然知之甚少。ORAI介导的Ca 2 + 信号传播到线粒体中以调节生物能量学、生物发生和凋亡。 线粒体Ca 2+摄取在线粒体基质内解码，有效地偶联PM 受体激活代谢活性。线粒体Ca 2+摄取和排出是由 线粒体Ca ~（2+）单向转运体（MCU）和Na ~+/Ca ~（2+）交换体（NCLX）。的 MCU/NCLX和STIM/奥赖的相互调节机制及收敛性 这些机制在控制代谢、肥胖和血管疾病中的作用尚不清楚。 我们的动物模型和令人信服的体内和体外数据的结果支持特定的作用 对于ER-PM-线粒体连接处的这些Ca 2+信号分子，它们在那里调节细胞增殖， 在内皮功能障碍、肥胖、高血压中至关重要的信号传导和代谢 和血管重塑我们的研究旨在了解：1）基本的 这些Ca 2+通道的组织、激活和调节机制及其 通讯机制;和2）这些Ca 2+信号蛋白的作用， 血管和代谢疾病的病理/生理学。我们的研究将提供新的见解， 这些分子在控制生理的代谢和信号通路中的确切作用 和病理生理学，并将为疾病治疗开辟新的途径。

Project Summary Our studies integrate fundamental biochemical and biophysical basis of Ca2+ channel activity with animal models of human diseases. We seek an understanding of how native channels are constructed, activated and regulated, how they control important functions in physiological systems and how their altered function drives disease. We are focused on the Ca2+ signaling proteins, ORAI, STIM, MCU and NCLX. ORAI channels are encoded by three separate genes (Orai1-3) and activated by the endoplasmic reticulum (ER) Ca2+ sensing proteins STIM (STIM1- 2). ORAI represent a family of highly Ca2+ selective channels in the plasma membrane (PM) of virtually all cells. The founding member of this family, ORAI1 physically interacts with STIM1 in ER-PM junctions, to mediate store-operated Ca2+ entry (SOCE). SOCE is critical in controlling many physiological functions including secretion, migration and proliferation in virtually all cell types. However, the physiological roles of ORAI2, ORAI3 and the mammalian-specific translational variant of ORAI1 called ORAI1α remain poorly understood. ORAI-mediated Ca2+ signals propagate into mitochondria to regulate both bioenergetics, biogenesis and apoptosis. Mitochondrial Ca2+ uptake is decoded within the mitochondrial matrix, effectively coupling PM receptor activation to metabolic activity. Mitochondrial Ca2+ uptake and extrusion are mediated by the mitochondrial Ca2+ uniporter (MCU) and Na+/Ca2+ exchanger (NCLX), respectively. The mechanisms of reciprocal regulation between MCU/NCLX and STIM/ORAI and the convergence of these mechanisms in the control of metabolism, obesity and vascular disease are unknown. Results from our animal models and our compelling in vivo and in vitro data support specific roles for these Ca2+ signaling molecules at the ER-PM-mitochondria nexus, where they regulate cell signaling and metabolism of critical importance in endothelial dysfunction, obesity, hypertension and vascular remodeling. Our studies are aimed at understanding: 1) The fundamental mechanisms of organization, activation and regulation of these Ca2+ channels and their mechanisms of communication; and 2) The role of these Ca2+ signaling proteins in patho/physiology of vascular and metabolic disease. Our studies will provide novel insights into the precise role of these molecules in metabolic and signaling pathways controlling physiology and pathophysiology and will lead to novel avenues for disease therapy.