Mechanisms Underlying Vascular Aging

血管老化的机制

• 批准号: 9924229
• 负责人: JAMES Kuang-Jan LIAO
• 金额: $ 5.54万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-22 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924229
• 关键词: Affect; African; African American; Aging; Award; Bioinformatics; Blood Vessels; Cardiovascular Diseases; Caucasians; Code; Diagnosis; Disease; Elderly; Epidemic; Etiology; Genetic; Genetic Variation; Genomics; Human; In Vitro; Incidence; Individual; Intervention; Knowledge; Mediating; Molecular; Obesity; Pathogenesis; Phosphotransferases; Play; Population; Prevention; ROCK1 gene; Risk; Risk Factors; Role; Smoking; Translational Research; Variant; Vascular Diseases; Vasomotor; cardiovascular risk factor; career development; clinical practice; fasudil; genetic variant; genomic variation; health disparity; improved; inhibitor/antagonist; parent grant; precision medicine; research and development; rho; statistics; stroke patient; systolic hypertension; targeted treatment

Abstract Aortic stiffness is considered a growing epidemic and has emerged as an important risk factor for various cardiovascular diseases (CVD). African Americans have the highest incidence rates of CVD and studies have shown that aortic stiffness is also higher among AAs compared to Caucasians. Very little is known about the molecular mechanism of aortic stiffness in AAs. A potential cause for the increased risk of aortic stiffness in African Americans is genetics. Populations of African ancestry have more genetic variation and less correlation between physically close genetic variants than other populations which means that, in addition to shared variation across populations, there remains population-specific genetic variation that contributes to disease. The rho-associated coiled-coil forming kinases (ROCK1 and ROCK2) have been shown to play a critical role in many cardiovascular diseases and increased ROCK activity has been associated with advancing age, systolic hypertension, and other cardiovascular risk factors such as obesity and smoking. Furthermore, increased ROCK activity correlates with aortic stiffness and vascular dysfunction, and treatment with the ROCK inhibitor, fasudil, improves vasomotor function in humans. These findings suggest that ROCKs may play an important role in the pathogenesis of aortic stiffness. But our knowledge of the molecular mechanisms regulating ROCK activity is limited and furthermore, we do not know if there are population-specific genetic modifiers of ROCK activity. The focus of the proposed study is to identify genetic modifiers of ROCK activity and elucidate molecular mechanisms leading to aortic stiffness in African Americans. Increased ROCK activity may increase risk of aortic stiffness in African Americans and furthermore, genetic modifiers of ROCK activity may be associated with aortic stiffness. The results generated from our project will advance our understanding of genetic modifiers of ROCK activity and risk factors of aortic stiffness in African Americans. Translational research that integrates population-specific genomic variation and complexity has tremendous potential to reduce health disparities and improve clinical practice. This study will harness the latest advances in bioinformatics and genomics to better understand the etiology of ROCK activity and aortic stiffness and serve as a platform so that prevention, diagnosis and treatment are precisely tailored to individuals – making precision medicine a reality for African American stroke patients.

摘要 主动脉僵硬被认为是一种日益增长的流行病，并已成为各种疾病的重要风险因素。 心血管疾病（CVD）。非裔美国人的心血管疾病发病率最高，研究表明， 表明与白种人相比，AA中的主动脉僵硬度也更高。关于这一点，我们知之甚少。 AA中主动脉僵硬的分子机制。主动脉僵硬风险增加的一个潜在原因是 美国人是基因。非洲血统的人群有更多的遗传变异和更少的相关性 在物理上接近的遗传变异比其他人群，这意味着，除了共享， 尽管存在群体间的变异，但仍存在导致疾病的群体特异性遗传变异。 rho相关卷曲螺旋形成激酶（ROCK 1和ROCK 2）已被证明在以下方面发挥关键作用： 许多心血管疾病和增加的ROCK活性与年龄的增长、收缩压的升高、 高血压和其他心血管危险因素，如肥胖和吸烟。此外，增加了 ROCK活性与主动脉僵硬和血管功能障碍相关，并且用ROCK抑制剂治疗， 法舒地尔改善人体血管功能。这些发现表明，ROCK可能发挥重要作用， 在主动脉僵硬发病机制中的作用。但是我们对ROCK调控的分子机制的了解 活性是有限的，此外，我们不知道是否有人群特异性的ROCK基因修饰剂 活动这项研究的重点是确定ROCK活性的遗传修饰剂， 导致非裔美国人主动脉僵硬的分子机制。ROCK活性增加可能会增加 非裔美国人主动脉僵硬的风险，此外，ROCK活性的遗传修饰剂可能是 与主动脉僵硬有关我们的项目产生的结果将促进我们对 非裔美国人ROCK活性的遗传修饰因子和主动脉僵硬的危险因素。平移 整合群体特异性基因组变异和复杂性的研究具有巨大的潜力， 减少健康差距，改善临床实践。这项研究将利用最新的进展， 生物信息学和基因组学，以更好地了解ROCK活动和主动脉僵硬的病因， 作为一个平台，使预防，诊断和治疗精确地针对个人， 精准医疗为非裔美国中风患者提供了现实。