Genes and miRNAs controlled by ORAI3 in cardiovascular remodeling

ORAI3在心血管重塑中控制的基因和miRNA

基本信息

批准号：
9042557
负责人：
DJAMEL LEBECHE
金额：
$ 26.36万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042557
关键词：
Aging Animal Model Animals Automobile Driving Biogenesis Biological Process Birth Blood Vessels Ca(2+)-Transporting ATPase Calcium Calcium ion Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cations 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 Pathway interactions 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 migration novel novel therapeutics older patient prevent programs public health relevance receptor response sensor stressor targeted treatment transcription factor transcriptome sequencing

项目摘要

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，心脏和血管系统发生重塑，并逐渐导致形状和功能的变化。在细胞水平上，这种病理重塑是由细胞内信号通路异常启动和维持的，特别是那些由钙 (Ca2+)2 控制的信号通路。 Ca2+ 进入心血管肌细胞（即心肌细胞；CM 和血管平滑肌细胞；VSMC）3-5。该来源由 STromal 相互作用分子 1 (STIM1)（一种主要在内质网表达的 Ca2+ 传感器）组成的复合物控制。 (ER) 膜，与 Ca2+ 选择性质膜 (PM) 通道新家族 Orai 家族（Orai1 至 3）相互作用并激活。 STIM1/Orai1-3 信号传导范式可以形成：i) 由 ER Ca2+ 储存耗尽（Orai1 同聚物）激活的 PM Ca2+ 通道，称为 Ca2+ 释放激活的 Ca2+ (CRAC) 通道，或 ii) 从胞浆激活的与储存无关的 Ca2+ 通道由花生四烯酸代谢物白三烯 C4 (LTC4) 旁边并由 Orai1 和 Orai3 的异多聚体介导（命名为 LRC，表示 LTC4 调节的 Ca2+）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 Ca2+ 信号传导的出现，该信号传导与基因转录特异性耦合并构成相关表型变化的基础。与心脏和血管重塑（即分别 CM 生长 - 心脏肥大和 VSMC 增殖 - 血管狭窄）3-5。该项目的目标是表征心血管系统中由 STIM1/Orai 复合物的不同元件具体控制的分子过程。是哺乳动物独有的，是病理性心血管肌细胞中出现的 STIM1 依赖的、不依赖于钙离子库的 Ca2+ 选择性电流的关键组成部分，因此我们追求 Orai3 通道更具体地调节心血管过程中激活的关键通路和基因网络。为了促进细胞生长、增殖和存活进行重塑，我们建议比较来自 Stim1 和 Orai3 组织特异性敲除小鼠和野生型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。总之，这些探索性结果将支持 Orai3 靶向与年龄相关的心血管重塑。