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Genetic insights into cardiovascular function and disease

对心血管功能和疾病的遗传学见解

基本信息

批准号：
7594435
负责人：
PAUL M. HWANG
金额：
$ 241.41万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

We are focusing on a novel pathway that regulates mitochondrial function and cardiovascular exercise capacity with implications for tumorigenesis. We have recently shown that the tumor suppressor gene p53 balances the energy generated by respiration and glycolysis and that this effect is primarily mediated through a p53 transcriptional target gene involved in cytochrome c oxidase complex assembly. Interestingly, mice deficient in p53 display profound deficiencies in aerobic exercise capacity revealing a new function for a well-studied gene mainly associated with cell cycle and genomic regulation. This finding also offers possible molecular explanations for some of our previous observations of p53 dependent oxidant generation and heart failure by chemotherapeutic agents. We are further characterizing our preliminary findings, and we are initiating studies to translate some of these basic observations to human studies. Our laboratory is also examining easily accessible human cells important for atherosclerosis to gain new insights into this cardiovascular disease. Using unbiased approaches, we have identified monocyte and macrophage transcriptional regulators as reactive markers and mediators of disease. We are performing studies to determine their clinical utility as markers and to elucidate their role as disease mediators using patient samples and model systems.

我们正专注于一种新的途径，调节线粒体功能和心血管运动能力与肿瘤发生的影响。我们最近表明，肿瘤抑制基因p53平衡呼吸和糖酵解产生的能量，这种效果主要是通过参与细胞色素c氧化酶复合物组装的p53转录靶基因介导的。有趣的是，缺乏p53的小鼠在有氧运动能力方面表现出严重的缺陷，这揭示了一个主要与细胞周期和基因组调控相关的已充分研究的基因的新功能。这一发现也为我们以前观察到的化疗药物引起的p53依赖性氧化剂生成和心力衰竭提供了可能的分子解释。我们正在进一步描述我们的初步发现，我们正在启动研究，将这些基本观察转化为人类研究。我们的实验室还在研究容易获得的对动脉粥样硬化很重要的人类细胞，以获得对这种心血管疾病的新见解。使用公正的方法，我们已经确定单核细胞和巨噬细胞的转录调节因子作为反应性标志物和介质的疾病。我们正在进行研究，以确定其作为标记物的临床效用，并使用患者样本和模型系统阐明其作为疾病介质的作用。