Vitamin D Status, Inflammation and Cardiac Risk in HIV

描述(申请人提供)：这个为期五年的职业发展奖的总体目标是1。)通过高级教学课程、结构化指导和进行/分析临床研究研究，使候选人能够作为一名独立的临床研究人员进行职业发展；以及更好地将维生素D状态定义为艾滋病毒相关心血管疾病(CVD)的介体，并确定维生素D状态是否改变了瑞舒伐他汀对艾滋病毒相关心血管疾病风险的影响。携带艾滋病毒的成年人患心血管疾病的风险比普通人群更高。维生素D缺乏在艾滋病毒中很常见，在普通人群中似乎在全身炎症和心血管疾病中发挥关键作用，但在艾滋病毒中尚未得到很好的研究。降低艾滋病毒中心血管疾病风险的战略为初级疾病预防提供了机会--这是一种替代现有疾病治疗的重要公共卫生选择，与NHLBI的使命密切相关，即促进心脏病的预防和治疗，增强所有人的健康，使他们能够活得更长、更有成就感。候选人将进行两项独立但免费的研究，一项一视同仁的队列研究和一项随机临床试验，这两项试验将嵌入两项已经资助的正在进行的研究中。候选人提案的具体目标是：1.1.评估维生素D状态对HIV感染者开始抗逆转录病毒治疗(ART)前后以及年龄、性别和种族匹配的HIV非感染者颈动脉内膜中层厚度(CIMT)进展和促炎生物标志物的影响；评估长期服用瑞舒伐他汀对艾滋病病毒感染者维他命D水平的影响。为了确定维生素D状态是否改变了瑞舒伐他汀对心血管疾病替代标记物、促炎生物标记物和稳定ART中HIV感染成年人的胆固醇水平的影响。终点将包括已建立的心血管疾病替代标志物，即超声测量的CIMT、CT扫描测量的冠状动脉钙化评分、超声测量的肱动脉血流介导的扩张，以及炎症、内皮激活、凝血和氧化等几个重要的生物标记物。统计分析将包括多元线性回归和混合效应建模。候选人将由Grace McComsey博士领导的多学科团队指导，Grace McComsey博士是国际公认的艾滋病毒相关代谢并发症(包括心血管疾病)临床研究员。候选人通过获得流行病学硕士学位和迄今专注于艾滋病毒相关心血管疾病领域的研究项目和改善这一风险的目标，表现出对临床研究事业的奉献精神。这一职业发展奖将为候选人追求独立的研究生涯奠定基础，该研究致力于更好地了解艾滋病毒相关心血管疾病的病理生理学和目标，以减少随后与艾滋病毒相关的心血管疾病的发病率和死亡率。

DESCRIPTION (provided by applicant): The overall aims of this five-year career development award are to 1.) enable the candidate's career development as an independent clinical researcher through advanced didactic coursework, structured mentoring and conduct/analysis of a clinical research study; and 2.) better define vitamin D status as a mediator of HIV-related cardiovascular disease (CVD) as well as to determine if vitamin D status changes the effect of rosuvastatin on HIV-related CVD risk. Adults living with HIV are at higher risk than the general population for CVD. Vitamin D deficiency is common in HIV, and appears to play a critical role in systemic inflammation and CVD in the general population, but is not well studied in HIV. Strategies to modify the risk of CVD in HIV present an opportunity for primary disease prevention-an important public health alternative to the treatment of established disease and closely aligned with the mission of NHLBI "to promote the prevention and treatment of heart disease and enhance the health of all individuals so that they can live longer and more fulfilling lives." The candidate will conduct two separate, but complimentary studies one ambispective, cohort study and one randomized clinical trial that will be embedded into two already funded, ongoing studies. The specific aims of the candidates proposal are: 1.) to evaluate the effect over time of vitamin D status on carotid intima media thickness (cIMT) progression and proinflammatory biomarkers in HIV- infected adults before and after initiating antiretroviral therapy (ART) and in age-, sex- and race-matched HIV- uninfected adults; 2.) to evaluate the impact over time of rosuvastatin on vitamin D levels in HIV-infected adults on stable ART; and 3.) to determine if vitamin D status modifies the effect of rosuvastatin on surrogate markers of CVD, proinflammatory biomarkers and cholesterol levels in HIV-infected adults on stable ART. Endpoints will include established surrogate markers of CVD, i.e., cIMT measured by ultrasound, coronary artery calcium score measured by CT scanning, flow mediated dilation of the brachial artery measured by ultrasound, and several important biomarkers of inflammation, endothelial activation, coagulation and oxidation. Statistical analyses will include multiple linea regression and mixed effects modeling. The candidate will be mentored by a multidisciplinary team led by Dr. Grace McComsey, an internationally-recognized clinical researcher in HIV- related metabolic complications, including cardiovascular disease. The candidate has shown a dedication to a career in clinical research through receipt of a Master's in Epidemiology and profile of research projects to date focused in the area of HIV-related CVD and targets to ameliorate this risk. This Career Development Award will provide the foundation for the candidate to pursue an independent research career dedicated to better understanding the pathophysiology of and targets to reduce subsequent morbidity and mortality associated with HIV-related CVD.