Ca2+ signaling Networks in Health and Disease

健康和疾病中的 Ca2 信号网络

• 批准号: 10539350
• 负责人: Mohamed Trebak
• 金额: $ 90.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-06 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539350
• 关键词: Animal Model; Apoptosis; Biochemical; Bioenergetics; Biogenesis; Biophysics; Calcium; Calcium Channel; Calcium Signaling; Cardiovascular Diseases; Cell membrane; Cells; Cellular Metabolic Process; Communication; Coupling; Data; Disease; Endoplasmic Reticulum; Family; Family member; Functional disorder; Genes; Growth; Health; Hypertension; In Vitro; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Matrix; Molecular; Obesity; Pathologic; Physiological; Physiology; Play; Proliferating; Proteins; Receptor Activation; Regulation; Role; STIM1 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; System; Variant; Vascular Diseases; Vascular remodeling; calcium uniporter; cell motility; cell type; endothelial dysfunction; human disease; human model; in vivo; insight; migration; mitochondrial membrane; novel; novel therapeutics; prevent; uptake; virtual

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.

项目概要 我们的研究将 Ca2+ 通道活性的基本生化和生物物理基础与 我们寻求了解人类疾病的动物模型。 构建、激活和调节，它们如何控制生理中的重要功能 系统及其功能如何驱动疾病。我们专注于 Ca2+ 信号传导。 ORAI、STIM、MCU 和 ORAI 通道蛋白由三个独立的基因编码。 (Orai1-3) 并由内质网 (ER) Ca2+ 传感蛋白 STIM (STIM1- 2) ORAI 代表质膜 (PM) 中的一系列高 Ca2+ 选择性通道。 ORAI1 是该家族的创始成员，几乎在所有细胞中都与 STIM1 发生物理相互作用。 ER-PM 连接，介导钙池操纵的 Ca2+ 进入 (SOCE) 对于控制至关重要。 许多生理功能，包括几乎所有细胞的分泌、迁移和增殖 然而，ORAI2、ORAI3 的生理作用是哺乳动物特有的。 ORAI1 的翻译变体 ORAI1α 仍知之甚少。 信号传播到线粒体中以调节生物能、生物发生和细胞凋亡。 线粒体 Ca2+ 摄取在线粒体基质内解码，有效耦合 PM 受体激活对代谢活动的影响是由线粒体 Ca2+ 摄取和排出介导的。 分别为线粒体 Ca2+ 单向转运蛋白 (MCU) 和 Na+/Ca2+ 交换器 (NCLX)。 MCU/NCLX与STIM/ORAI之间的相互调节机制及融合 这些机制在控制新陈代谢、肥胖和血管疾病方面的作用尚不清楚。 我们的动物模型的结果以及令人信服的体内和体外数据支持特定的作用 这些 Ca2+ 信号分子位于 ER-PM-线粒体连接处，在那里调节细胞 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 我们的研究旨在了解：1）基本原理。 这些 Ca2+ 通道的组织、激活和调节机制及其 通讯机制；2) 这些 Ca2+ 信号在蛋白质中的作用 我们的研究将为血管和代谢疾病的病理/生理学提供新的见解。 这些分子在控制生理学的代谢和信号通路中的精确作用 和病理生理学，并将带来疾病治疗的新途径。