Genes and miRNAs controlled by ORAI3 in cardiovascular remodeling

ORAI3在心血管重塑中控制的基因和miRNA

• 批准号: 9334046
• 负责人: DJAMEL LEBECHE
• 金额: $ 20.73万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334046
• 关键词: ATP phosphohydrolase; Aging; Animal Model; Animals; Automobile Driving; Biogenesis; Biological Process; Birth; Blood Vessels; Calcium; Calcium Channel; Calcium Signaling; Calcium ion; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cations; Cell Count; Cell membrane; Cell model; Complex; Computer Simulation; Couples; Data; Development; Disease model; Elements; Endoplasmic Reticulum; Family; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Growth; Heart Diseases; Heart Hypertrophy; Heart failure; Heterogeneity; Injury; Ion Channel; Knockout Mice; Laboratories; Lead; Ligation; Mammals; Mediating; Membrane; MicroRNAs; Molecular; Molecular Profiling; Mus; Muscle Cells; Names; Ontology; Operative Surgical Procedures; Pathologic; Pathway interactions; Pharmacotherapy; Phenotype; Physiological; Physiology; Process; Protein Isoforms; Proteins; Pump; Quality of life; Regulator Genes; Reporting; Research Proposals; Risk Factors; Role; STIM1 gene; Shapes; Side; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Stenosis; Stroke; Technology; Tissue Sample; Tissues; Vascular Diseases; Vascular Proliferation; Vascular Smooth Muscle; Vascular System; Vascular remodeling; Wild Type Mouse; age related; arachidonate; cell growth; cell type; differential expression; ion source; migration; new therapeutic target; novel therapeutics; older patient; prevent; programs; public health relevance; receptor; response; sensor; stressor; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant) Adverse cardiovascular remodeling is particularly prevalent in elderly patients, resulting in poor quality of life and devastating consequences. In response to various physiological and pathological stressors, the cardiac and vascular systems remodel with changes in shape and function that progressively lead to adverse cardiovascular outcomes1. At the cellular level, this pathological remodeling is initiated and sustained by abnormalities in intracellular signaling pathways especially those controlled by calcium (Ca2+)2. Recent studies from both our laboratories have identified a new source of Ca2+ entry in cardiovascular myocytes (i.e., cardiac myocytes; CMs and vascular smooth muscle cells; VSMCs)3-5. This source is controlled by a complex composed of STromal Interaction Molecule 1 (STIM1), a Ca2+ sensor mainly expressed at the endoplasmic reticulum (ER) membrane, which interacts with and activates a new family of Ca2+ selective plasma membrane (PM) channels, the Orai family (Orai1 through 3). The STIM1/Orai1-3 signaling paradigm can either form: i) PM Ca2+ channels activated by ER Ca2+ store depletion (Orai1 homomers) termed Ca2+ release-activated Ca2+ (CRAC) channels, or ii) store-independent Ca2+ channels activated from the cytosolic side by the arachidonate metabolite, leukotrieneC4 (LTC4) and mediated by heteromultimers of Orai1 and Orai3 (named LRC for LTC4-regulated Ca2+)3-7. In different cellular and animal models of cardiac and vascular disorders, we have demonstrated the emergence of the STIM/Orai-mediated Ca2+ signaling that specifically couples to gene transcription and underlies phenotypic changes associated with cardiac and vascular remodeling (i.e. CM growth - cardiac hypertrophy and VSMC proliferation - vascular stenosis respectively)3-5. The targeted manipulation of this local calcium source prevents adverse cardiac and vascular remodeling thus offering new therapeutic perspectives3-5. The goal of this project is the characterization of the molecular processes that are specifically controlled by the different elements of the STIM1/Orai complex in the cardiovascular system. Our recent data indicate that along with Orai1, Orai3, which is exclusive to mammals, is a key component of the STIM1-dependent store- independent Ca2+ selective currents that emerge in pathological cardiovascular myocytes. We thus hypothesize that Orai3 channels more specifically regulate key pathways and gene networks that are activated during cardiovascular remodeling in order to promote cell growth, proliferation and survival. We propose to compare the transcriptional signature of isolated cardiovascular myocytes (i.e., cardiac myocytes and arterial smooth muscle cells) from Stim1 and Orai3 tissue-specific knockout mice and from wild-type mice under normal and pathological conditions of cardiac and vessel remodeling. Together, these exploratory results will support Orai3 targeting in age-related cardiovascular remodeling.

 描述（由申请人提供）不良心血管重塑在老年患者中尤其普遍，导致生活质量差和毁灭性后果。为了应对各种生理和病理应激源，心脏和血管系统重塑，形状和功能发生变化，逐渐导致不良心血管结局1。在细胞水平上，这种病理性重塑是由细胞内信号传导途径的异常，特别是由钙（Ca 2+）2控制的信号传导途径的异常引发和维持的。我们两个实验室最近的研究已经确定了心血管肌细胞中Ca 2+进入的新来源（即，心肌细胞; CM和血管平滑肌细胞; VSMC）3-5。该来源由一种由STromal相互作用分子1（STIM 1）组成的复合物控制，STIM 1是一种主要在内质网（ER）膜上表达的Ca 2+传感器，它与一种新的Ca 2+选择性质膜（PM）通道家族（奥赖家族（Orai 1至3））相互作用并激活该家族。STIM 1/Orai 1 -3信号传导模式可以形成：i）通过ER Ca 2+库耗尽激活的PM Ca 2+通道（Orai 1同聚体）称为Ca 2+释放激活的Ca 2+（CRAC）通道，或ii）由花生四烯酸代谢物从胞质侧激活的非钙库依赖性Ca 2+通道，白三烯C4（LTC 4）和介导的Orai 1和Orai 3（命名为LRC的LTC 4调节的Ca 2+）的异多聚体3-7。在心脏和血管疾病的不同细胞和动物模型中，我们已经证明了STIM/Orai介导的Ca 2+信号传导的出现，其特异性地与基因转录偶联，并成为与心脏和血管重塑相关的表型变化的基础（即分别为CM生长-心脏肥大和VSMC增殖-血管狭窄）3-5。这种局部钙源的靶向操作可防止不利的心脏和血管重塑，从而提供新的治疗前景3 -5。该项目的目标是表征由心血管系统中STIM 1/奥赖复合物的不同元素具体控制的分子过程。我们最近的数据表明，沿着Orai 1，Orai 3，这是专为哺乳动物，是一个关键组成部分的STIM 1依赖性的非储存-非依赖性钙选择性电流，出现在病理性心血管心肌细胞。因此，我们假设Orai 3通道更特异性地调节在心血管重塑期间激活的关键通路和基因网络，以促进细胞生长、增殖和存活。我们建议比较分离的心血管肌细胞的转录特征（即，心肌细胞和动脉平滑肌细胞）。总之，这些探索性结果将支持Orai 3靶向年龄相关的心血管重塑。