MicroRNA as mediators of angiogenesis & ischemic myocardial repair

MicroRNA 作为血管生成的介质

基本信息

批准号：
9059179
负责人：
Muhammad Ashraf
金额：
$ 49.88万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-12 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9059179
关键词：
Affect Area Bone Marrow Cardiac Cardiac Myocytes Cell Survival Cell Therapy Cells Cellular biology Coronary Arteriosclerosis Data Development Endothelial Cells Engineering Environment Evaluation Event Extracellular Fluid Foundations Functional disorder Gap Junctions Gene Targeting Genetic Engineering Heart Heart failure Infarction Ischemia Mediating Mediator of activation protein Mesenchymal Stem Cells Messenger RNA MicroRNAs Molecular Molecular Biology Myocardial Myocardial Infarction Myocardial Ischemia Myocardial perfusion Myocardium Natural regeneration Pathology Play Positioning Attribute Proteins Reperfusion Injury Research Role Staging Stem cell transplant Stem cells Techniques Testing Therapeutic Tissues Translational Repression Transplantation Untranslated RNA Up-Regulation Ventricular Remodeling adult stem cell angiogenesis base blood vessel development cardiac regeneration cardiac repair cell injury coronary fibrosis design experience extracellular improved in vivo insight microvesicles molecular imaging novel therapeutics overexpression regenerative repaired stem cell biology stem cell therapy tissue repair transcription factor

项目摘要

DESCRIPTION (provided by applicant): Stem cell therapy is a putative treatment for end-stage heart failure. Bone marrow-derived mesenchymal stem cells (MSC) improve cardiac function following intramyocardial transplantation. Our previous study indicates that MSC preprogrammed to express GATA-4 (MSCGATA-4), a well-known cardiac transcription factor, significantly accelerate ischemic heart repair - by increasing MSC survival and differentiation, as well as angiogenesis. However, the mechanism is unclear. The recently discovered endogenous class of small non-coding RNAs, microRNAs (miRs), plays an important role in both cardiac protection and pathology associated with myocardial ischemia. Our preliminary data indicate that overexpression of GATA-4 in MSC modulates expression of several miRs which can then transfer from MSC into neighboring cardiomyocytes (CM). We propose the following two hypotheses: Hypothesis 1: Specific miRs and miR targeted genes mediate potent pro-survival and pro-angiogenic effects. Hypothesis 2: miRs in transplanted MSC transfer to neighboring host cells or the extracellular environment via gap junctions and microvesicles (MVs). The proposed study represents the first in- depth attempt to elucidate the mechanism by which GATA-4 overexpression in MSC regulates expression of specific miRs that, in turn, enhance angiogenesis and cardioprotection when these MSC are transplanted into ischemic myocardium. The results of these studies should (i) provide evidence that MSC besides their differentiation potential serve as an important delivery vehicle for cardioprotectve proteins and molecules in repair of ischemic myocardium; (ii) explore the impact of transfer of specific molecules from MSC to the extracellular fluid space via MVs, and directly into CM via gap junctions or other intercellular channels. These findings may not only highlight the molecular mechanisms of MSCGATA-4 - mediated angiogenesis, but may also help formulate a novel therapeutic strategy for ischemia and offer insight into the progression of myocardial remodeling.

描述（由申请人提供）：干细胞疗法是终末期心力衰竭的推定治疗方法。骨髓衍生的间充质干细胞（MSC）改善心脏内心脏移植后心脏功能。我们先前的研究表明，MSC预编程已表达GATA-4（MSCGATA-4），这是一种众所周知的心脏转录因子，通过增加MSC的存活率和分化，显着加速了缺血性心脏修复 - 以及血管生成。但是，该机制尚不清楚。最近发现的内源性小型非编码RNA MicroRNA（miRS）在与心肌缺血相关的心脏保护和病理学中起着重要作用。我们的初步数据表明，MSC中GATA-4的过表达调节了几种MIR的表达，然后可以从MSC转移到邻近的心肌细胞（CM）。我们提出以下两个假设：假设1：特定的miR和miR靶向基因介导有效的促生存和促血管生成作用。假设2：通过间隙连接和微泡（MVS）移植的MSC转移到相邻宿主细胞或细胞外环境中的miR。拟议的研究代表了阐明MSC中GATA-4过表达的机制的首次深度尝试，而MSC中的过表达调节了特定miR的表达，从而增强了当这些MSC移植到缺血性心肌中时增强血管生成和心脏保护。这些研究的结果应（i）提供证据，表明MSC除了分化潜力外是心脏保护蛋白和分子修复缺血性心肌的重要递送工具；（ii）探索通过MVS从MSC到细胞外流体空间转移的影响，并通过间隙连接或其他细胞间通道直接进入CM。这些发现不仅可以突出MSCGATA -4的分子机制 - 介导的血管生成，而且还可能有助于制定一种新型的缺血治疗策略，并深入了解心肌重塑的进展。