Mitochondrial regulation in cardiovascular and cancer biology

心血管和癌症生物学中的线粒体调节

• 批准号: 8746587
• 负责人: PAUL M. HWANG
• 金额: $ 99.55万
• 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/8746587
• 关键词: Aerobic Exercise; Affect; Biology; Cancer Biology; Cardiovascular system; Cell Respiration; Clinical Research; Development; Epidemiology; Exercise; Germ-Line Mutation; Goals; Health; Human; In Vitro; Incidence; Individual; Knockout Mice; Laboratory Finding; Li-Fraumeni Syndrome; Malignant Neoplasms; Metabolic; Mitochondria; Modeling; Molecular; Mutation; Regulation; Respiration; Syndrome; TP53 gene; Translating; Tumor Suppression; Tumor Suppressor Genes; Work; human subject; improved; in vivo Model; insight; mouse model; premature; prevent; tumorigenesis

We have shown that p53 promotes aerobic metabolism through its positive regulation of mitochondrial respiration. p53 null mice, a model of de novo tumorigenesis, display profound deficiencies in aerobic exercise capacity. Remarkably, the promotion of exercise capacity by a tumor suppressor gene in a mouse model parallels the human epidemiologic observation of a strong inverse relationship between exercise capacity and cancer incidence. We believe that these two independent observations may share a common mechanism for tumor suppression, therefore, we are investigating the regulation of mitochondrial function by p53 using in vitro and in vivo models. Additionally, we are studying cardiovascular and metabolic functions in individuals with Li-Fraumeni syndrome, a premature cancer syndrome caused by germline mutations in the p53 gene. The goal of this work is to derive basic insights that may assist in the development of new strategies for preventing cancer and improving cardiovascular health.

我们已经表明，p53通过其积极调节线粒体呼吸促进有氧代谢。 p53缺失小鼠是一种新生肿瘤发生模型，显示出有氧运动能力的严重缺陷。 值得注意的是，在小鼠模型中，肿瘤抑制基因对运动能力的促进与人类流行病学观察到的运动能力与癌症发病率之间存在强烈的负相关关系相平行。 我们认为这两个独立的观察结果可能具有共同的肿瘤抑制机制，因此，我们正在研究p53使用体外和体内模型对线粒体功能的调节。 此外，我们正在研究Li-Fraumeni综合征患者的心血管和代谢功能，Li-Fraumeni综合征是一种由p53基因生殖系突变引起的过早癌症综合征。 这项工作的目标是获得可能有助于制定预防癌症和改善心血管健康的新策略的基本见解。