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（由适用的）不良心血管重塑在老年患者中尤为普遍，导致生活质量差和毁灭性后果。为了响应各种物理和病理压力源，心脏和血管系统重塑了形状和功能变化，逐渐导致心血管不良结局1。在细胞水平上，该患者的重塑是由细胞内信号通路异常引发和维持的，尤其是钙（CA2+）2控制的患者。我们两个实验室的最新研究都确定了心血管肌细胞中Ca2+进入的新来源（即心肌细胞； CMS和血管平滑肌细胞； VSMCS）3-5。该源由由基质相互作用分子1（STIM1）组成的复合物控制，该络合物主要在内质网（ER）膜上表达的Ca2+传感器，该膜与Ca2+选择性质等浆膜（PM）通道（ORAI1家族）（ORAI1至3）相互作用并激活新的家族。 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 Orai1和Orai3的异型物（以LTC4调节的Ca2+为LRC）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.该局部钙源的有针对性操纵可防止心脏和血管重塑，从而提供新的治疗透视图3-5。该项目的目的是表征分子过程，这些过程由心血管系统中STIM1/ORAI复合物的不同元素专门控制。我们最近的数据表明，与哺乳动物独有的Orai1，Orai3一起是Stim1依赖的商店 - 独立CA2+选择性电流的关键组成部分，它们出现在病理心血管心肌细胞中。因此，我们假设ORAI3通道更具体地调节心血管重塑期间激活的关键途径和基因网络，以促进细胞生长，增殖和存活。我们建议比较来自STIM1和ORAI3组织特异性敲除小鼠的分离心血管肌细胞（即心肌细胞和动脉平滑肌细胞）的转录特征，以及在心脏和容器重塑的正常病理条件下野生型小鼠的转录。总之，这些探索性结果将支持与年龄相关的心血管重塑的ORAI3靶向。