Ca2+ signaling mechanisms in cardiac fibrosis

心脏纤维化中的 Ca2 信号传导机制

• 批准号: 7077778
• 负责人: Lixia Yue
• 金额: $ 36.13万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077778
• 关键词: acidosis; calcium channel; calcium flux; calcium indicator; cell proliferation; collagen; fibroblasts; fibrogenesis; fibrosis; genetically modified animals; heart cell; heart disorder; hydrogen peroxide; laboratory mouse; molecular pathology; oxidative stress; voltage /patch clamp; acidosis; calcium channel; calcium flux; calcium indicator; cell proliferation; collagen; fibroblasts; fibrogenesis; fibrosis; genetically modified animals; heart cell; heart disorder; hydrogen peroxide; laboratory mouse; molecular pathology; oxidative stress; voltage /patch clamp

DESCRIPTION (provided by applicant): Cardiac fibrosis is a major biological determinant in a variety of cardiac diseases including hypertrophy, heart failure, severe arrhythmias and sudden cardiac death. Early interference with fibroblast proliferation to limit fibrosis should be able to prevent fibrogenesis from further perpetuating cardiac diseases. However, Ca2+ signaling mechanisms in cardiac fibroblasts (CFs) have remained elusive. Our long-term goal is to investigate the Ca2+ signaling mechanisms in CFs and their potential roles in fibrotic heart diseases. We have previously cloned a novel bi-functional Ca2+-permeable ion channel TRPM7. Our recent preliminary data showed that: 1) TRPM7 is likely the molecular basis of native TRPM7L, the only Ca2+-permeable ion channel identified in the CFs to date; 2) TRPM7 inward currents can be drastically enhanced by a decrease in extracellular pH; 3) oxidative stress significantly increased TRPM7 inward currents; 4) chronic exposure to TGFb1 up-regulates TRPM7 expression in CFs. Given that acidosis, oxidative stress, and TGFb1 are potent stimuli in initiating fibrogenesis during myocardial injury/infarction, we hypothesize that TRPM7L is essential for Ca2+ signaling in CFs, and plays important roles in myocardial ischemia/infarction initiated fibrogenesis. We propose to: 1) determine if TRPM7 is the molecular basis of TRPM7L, and if TRPM7L underlies Ca2+ signaling mechanisms in CFs under oxidative stress and acidosis stimuli; 2) investigate if chronic fibrogenesis stimuli up-regulate TRPM7L; 3) determine if TRPM7L is essential for CFs' functions in responses to fibrogenesis stimuli. Patch-clamp, Ca2+ imaging, biochemical methods and gene knock-down will be used in this project to reveal the potential roles of TRPM7L-mediated Ca2+ signals in fibrogenesis cascade events. The results of the proposed studies will lead to a future in vivo study which is designed to evaluate potential roles of TRPM7 in cardiac fibrosis using TRPM7 knock out mice, and will ultimately provide clinical insights into therapeutic approaches for fibrosis associated cardiac diseases.

描述（由申请人提供）：心脏纤维化是多种心脏疾病的主要生物学决定因素，包括肥大，心力衰竭，严重的心律失常和猝死。早期干扰成纤维细胞增殖以限制纤维化，应能够防止进一步延伸心脏疾病的纤维发生。但是，心脏成纤维细胞（CFS）中的Ca2+信号传导机制仍然难以捉摸。我们的长期目标是研究CFS中的Ca2+信号传导机制及其在纤维化心脏病中的潜在作用。我们以前已经克隆了一种新型的双功能Ca2+可渗透离子通道TRPM7。我们最近的初步数据表明：1）TRPM7可能是天然TRPM7L的分子基础，这是迄今为止CFS中唯一识别的Ca2+可渗透离子通道； 2）TRPM7内流电流可以通过细胞外pH值的减少来大大增强； 3）氧化应激显着增加了TRPM7的内向电流； 4）长期暴露于TGFB1上的上调CFS中的TRPM7表达。鉴于酸中毒，氧化应激和TGFB1是在心肌损伤/梗死过程中启动纤维发生的有效刺激，因此我们假设TRPM7L对于CFS中的Ca2+信号是必不可少的，并且在心肌缺血/梗死开始纤维纤维化中起着重要的作用。我们建议：1）确定TRPM7是否是TRPM7L的分子基础，以及在氧化应激和酸中毒刺激下，CFS中的CA2+信号传导机制是否是CA2+信号传导机制； 2）研究慢性纤维发生刺激是否上调TRPM7L； 3）确定TRPM7L对于CFS对纤维发生刺激的响应中的功能是否必不可少。该项目将使用贴片钳，Ca2+成像，生化方法和基因敲低，以揭示TRPM7L介导的Ca2+信号在纤维化级联事件中的潜在作用。拟议研究的结果将导致未来的体内研究，旨在使用TRPM7敲除小鼠评估TRPM7在心脏纤维化中的潜在作用，并最终将提供对纤维化相关心脏疾病的治疗方法的临床见解。