Gene 33 in Ischemic Cardiomyopathy

缺血性心肌病中的基因 33

基本信息

批准号：
7239208
负责人：
DAZHONG XU
金额：
$ 6.6万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7239208
关键词：
Acute Affect Aging-Related Process Apoptosis Apoptotic BCL-2 Protein BCL2 gene Binding Blood flow Brain Hypoxia-Ischemia Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cardiovascular Diseases Caspase Chronic Chronic Disease Condition Country Cytochromes DNA biosynthesis DNA chemical synthesis Diabetic Nephropathy Disease Disruption ERG gene Environment Epidermal Growth Factor Receptor Equilibrium ErbB Receptor Family Protein Extracellular Signal Regulated Kinases Feedback Gene Expression Gene Silencing Genes Goals Grant Growth Factor Heart Heart Diseases Heart failure Hypoxia Injury Insulin-Like-Growth Factor I Receptor Intervention Ischemia Knockout Mice Left Ventricular Function Link Liver diseases MEKs Mediating Mediator of activation protein Medical center Mitochondria Mitogen-Activated Protein Kinases Molecular Mus Myocardial Infarction Names Neonatal New England Phosphotransferases Protein Biosynthesis Protein Family Protein Overexpression Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-akt Publishing Purpose RNA Interference Rattus Receptor Protein-Tyrosine Kinases Regulation Reperfusion Injury Research Research Institute Research Project Grants Role Signal Pathway Signal Transduction Stimulus Stress Testing Tissues Transgenic Organisms adenoviral-mediated age related aging population career cytokine extracellular gene function human MAP2K1 protein in vivo inhibitor/antagonist insight member novel novel therapeutics programs response size therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The primary purpose of this R03 small research grant is to provide short-term support for the PI to further develop a promising ongoing research project on the function of Gene 33 in ischemic cardiomyopathy. Our goal is to develop the project into a full size research program that can successfully compete for R01 support. This grant would also help the PI to develop a research career on age-related heart diseases. The Molecular Cardiology Research Institute at the Tufts-New England Medical Center provides an excellent physical and intellectual environment for perusing research on cardiovascular diseases. Cardiomyocyte apoptosis is closely linked to age-related heart conditions, such as myocardial infarction, ischemia/reperfusion injury and heart failure. Evidence shows that cardiomyocyte apoptosis involves the dysfunctional regulation of multiple intracellular signaling pathways, which function to maintain a balance between apoptotic and survival signals. Despite numerous research efforts, the molecular mechanisms behind cardiomyocyte apoptosis in response to ischemic insults are still poorly understood. Published studies have focused mostly on conventional mediators of apoptosis. Transcriptionally induced mediators of cardiomyocyte apoptosis are much poorly understood. These mediators could be more relevant to cardiomyocyte apoptosis in chronic disease conditions related to the aging process. The focus of the proposed study will be on the role of Gene 33 in mouse cardiac ischemia. We have discovered that Gene 33 is a mediator of cardiomyocyte apoptosis induced by hypoxia and hypoxia/reoxygenation. Gene 33 is transcriptionally induced by hypoxia in cardiomyocytes and by ischemic stresses in murine hearts. Gene 33 inhibits AKT and ERK activition mediated by ErbB and IGF-1 receptor tyrosine kinase signaling. We also find that over- expression of Gene 33 in neonatal rat cardiomyocytes strongly induces apoptosis. These results suggest a significant role of Gene 33 in cardiomyocyte apoptosis in vivo. We hypothesize that Gene 33 mediates cardiomyocyte apoptosis in response to ischemic injury in vivo. We accordingly propose two specific aims to test our hypothesis: 1) Characterize the effect of gene 33 overexpression on the mouse heart. 2) Explore how disruption of gene 33 influences cardiomyocyte apoptosis and cardiac function following ischemic injury to the mouse heart. We believe that this study will provide significant new insight into the understanding of cardiomyocyte apoptosis and ischemic cardiomyopathy and contribute to identifying novel therapeutic targets in age-related heart diseases. Relevance: This research project studies a potentially important molecular mediator of ischemic cardiomyopathy. Ischemic cardiomyopathy is a heart condition (caused by restriction of blood flow to the heart) that is especially prevalent in the aging population and affects millions of people in this country. This study would provide significant new insight into understanding the mechanisms of the disease and contribute to identification of novel therapeutic targets.

描述（由申请人提供）：R03 小额研究资助的主要目的是为 PI 提供短期支持，以进一步开发一项有前途的正在进行的关于基因 33 在缺血性心肌病中的功能的研究项目。我们的目标是将该项目发展成为一个能够成功竞争 R01 支持的完整规模的研究计划。这笔赠款还将帮助 PI 发展与年龄相关的心脏病的研究事业。塔夫茨-新英格兰医学中心的分子心脏病学研究所为心血管疾病的研究提供了良好的物质和智力环境。心肌细胞凋亡与年龄相关的心脏病密切相关，例如心肌梗塞、缺血/再灌注损伤和心力衰竭。有证据表明，心肌细胞凋亡涉及多个细胞内信号通路的功能失调调节，这些信号通路的作用是维持细胞凋亡和生存信号之间的平衡。尽管进行了大量的研究工作，但心肌细胞凋亡响应缺血性损伤背后的分子机制仍然知之甚少。已发表的研究主要集中在细胞凋亡的常规介质上。对转录诱导的心肌细胞凋亡介质知之甚少。这些介质可能与衰老过程相关的慢性疾病中的心肌细胞凋亡更相关。拟议研究的重点是基因 33 在小鼠心脏缺血中的作用。我们发现基因33是缺氧和缺氧/复氧诱导的心肌细胞凋亡的介质。基因 33 是由心肌细胞缺氧和小鼠心脏缺血应激诱导转录的。基因 33 抑制 ErbB 和 IGF-1 受体酪氨酸激酶信号传导介导的 AKT 和 ERK 激活。我们还发现新生大鼠心肌细胞中基因33的过度表达强烈诱导细胞凋亡。这些结果表明基因 33 在体内心肌细胞凋亡中发挥重要作用。我们假设基因 33 介导心肌细胞凋亡以响应体内缺血性损伤。因此，我们提出两个具体目标来检验我们的假设：1）表征基因 33 过度表达对小鼠心脏的影响。 2) 探索基因 33 的破坏如何影响小鼠心脏缺血损伤后的心肌细胞凋亡和心脏功能。我们相信，这项研究将为理解心肌细胞凋亡和缺血性心肌病提供重要的新见解，并有助于确定与年龄相关的心脏病的新治疗靶点。相关性：该研究项目研究缺血性心肌病的潜在重要分子介质。缺血性心肌病是一种心脏病（由心脏血流受限引起），在老龄化人口中尤其普遍，影响着该国数百万人。这项研究将为理解该疾病的机制提供重要的新见解，并有助于确定新的治疗靶点。