Ca2+ Signaling Networks in Health and Disease

项目摘要 我们的研究将钙通道活性的基本生化和生物物理基础与 人类疾病的动物模型。我们寻求了解本地频道是如何 构建、激活和调节，它们如何控制重要的生理功能 以及它们改变的功能是如何导致疾病的。我们关注的是钙信号转导 蛋白质、ORAI、STIM、MCU和NCLX。Orai通道由三个独立的基因编码 (ORAI1-3)，并由内质网(ER)钙感应蛋白STIM(STIM1-)激活。 2)。ORAI代表细胞膜(PM)上的一组高选择性钙通道。 几乎所有的细胞。这个家族的创始成员ORAI1与STIM1在 ER-PM连接，介导钙离子内流(SOCE)。SOCE在控制中至关重要 几乎所有细胞的许多生理功能，包括分泌、迁移和增殖 类型。然而，ORAI2、ORAI3和哺乳动物特有的 被称为ORAI1α的ORAI1的翻译变体仍然知之甚少。Orai介导的钙离子通道 信号传播到线粒体，调节生物能量学、生物发生和细胞凋亡。 线粒体钙摄取在线粒体基质中被解码，有效地偶联PM 受体激活对代谢活性的影响。线粒体钙摄取和排泄是由 线粒体钙单转运体(MCU)和钠/钙交换器(NCLX)。这个 MCU/NCLX与STIM/ORAI的相互调节机制及其收敛 在这些机制中，控制新陈代谢、肥胖和血管疾病的机制尚不清楚。 我们动物模型的结果和我们令人信服的体内和体外数据支持特定的作用 对于这些位于内质网-质膜-线粒体网络的钙信号分子，它们在那里调节细胞 信号和代谢在内皮功能障碍、肥胖和高血压中的关键作用 和血管重塑。我们的研究旨在理解：1)根本 这些钙通道的组织、激活和调节机制及其相互作用 通讯机制；以及2)这些钙信号蛋白在 血管和代谢疾病的病理学/生理学。我们的研究将为我们提供新的见解 这些分子在控制生理学的代谢和信号通路中的确切作用 和病理生理学，并将导致疾病治疗的新途径。

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.