Genetic insights into cardiovascular function and disease

我们正在关注调节线粒体功能和心血管运动能力与肿瘤发生的新途径。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。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，这揭示了一个被充分研究的主要与细胞周期和基因组调控相关的基因的新功能。这一发现也为我们之前观察到的化疗药物对p53依赖性氧化剂生成和心力衰竭的影响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，将这些基本观察结果转化为人类研究。

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.