Genetic insights into cardiovascular function and disease

对心血管功能和疾病的遗传学见解

• 批准号: 7735016
• 负责人: PAUL M. HWANG
• 金额: $ 197.67万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7735016
• 关键词: Aerobic Exercise; Atherosclerosis; Biological; Biological Models; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Cycle; Cells; Clinical; Complex; Disease; Exercise; Gene Targeting; Generations; Genes; Genetic; Genomics; Glycolysis; Goals; Health; Heart failure; Human; Laboratories; Mediating; Mediator of activation protein; Mitochondria; Molecular; Mus; Oxidants; Pathway interactions; Patients; Protein p53; Regulation; Regulatory Pathway; Respiration; Role; Sampling; Screening procedure; TP53 gene; Translating; Tumor Suppressor Genes; cancer prevention; chemotherapeutic agent; cytochrome c oxidase; energy balance; human study; human subject; improved; insight; macrophage; monocyte; mouse model; novel; tumorigenesis

We are focusing on a novel pathway that regulates mitochondrial function and cardiovascular exercise capacity that may have 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. 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 offers possible molecular explanations for some of our previous observations of p53 dependent oxidant generation and heart failure by chemotherapeutic agents and raises new questions. We are further characterizing our preliminary findings, and we are initiating human studies to translate some of these basic observations. 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.

我们正在关注一种调节线粒体功能和心血管运动能力的新途径，这可能对肿瘤发生有影响。我们最近的研究表明，肿瘤抑制基因p53平衡呼吸和糖酵解产生的能量，这种作用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。缺乏p53的小鼠表现出有氧运动能力的严重缺陷，揭示了一个主要与细胞周期和基因组调控相关的基因的新功能。这一发现为我们之前观察到的p53依赖性氧化剂生成和化疗药物引起的心力衰竭提供了可能的分子解释，并提出了新的问题。我们正在进一步描述我们的初步发现，我们正在启动人体研究，以转化这些基本观察结果。

项目成果

Evaluation of pulsed Doppler tissue velocity imaging for assessing systolic function of murine global heart failure.

脉冲多普勒组织速度成像评估小鼠整体心力衰竭收缩功能的评估。

• DOI: 10.1016/j.echo.2004.08.038
• 发表时间: 2005
• 期刊: Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography
• 作者: Matoba,Satoaki;Hwang,PaulM;Nguyen,Tammy;Shizukuda,Yukitaka
• 通讯作者: Shizukuda,Yukitaka