Vitamin D Status, Inflammation and Cardiac Risk in HIV

描述（由申请人提供）：这项为期五年的职业发展奖励的总体目标是：1.通过先进的教学课程，结构化的指导和临床研究的进行/分析，使候选人成为独立的临床研究人员；2)更好地定义维生素D状态作为hiv相关心血管疾病（CVD）的中介，以及确定维生素D状态是否会改变瑞舒伐他汀对hiv相关CVD风险的影响。携带艾滋病毒的成年人患心血管疾病的风险高于一般人群。维生素D缺乏在艾滋病毒中很常见，似乎在普通人群的全身性炎症和心血管疾病中起着关键作用，但在艾滋病毒中尚未得到很好的研究。调整艾滋病毒引起的心血管疾病风险的策略为预防原发性疾病提供了机会，这是治疗既定疾病的重要公共卫生替代方案，与NHLBI的使命“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、更充实”密切相关。候选人将进行两项独立但互补的研究，一项是双视角队列研究，一项是随机临床试验，这两项研究将嵌入两项已经获得资助的正在进行的研究中。候选方案的具体目的是：1.评估维生素D状态随时间推移对HIV感染成人在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未感染成人颈动脉内膜中膜厚度（cIMT）进展和促炎生物标志物的影响；2.)评估瑞舒伐他汀对成年hiv感染者维生素D水平随时间变化对稳定抗逆转录病毒治疗的影响；3.)确定维生素D状态是否会改变瑞舒伐他汀对稳定抗逆转录病毒治疗中hiv感染成人心血管疾病、促炎生物标志物和胆固醇水平的替代标志物的影响。终点将包括CVD的既定替代标志物，即超声测量的cIMT， CT扫描测量的冠状动脉钙评分，超声测量的肱动脉血流介导的扩张，以及炎症、内皮活化、凝血和氧化等几个重要的生物标志物。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HIV相关代谢并发症（包括心血管疾病）的临床研究员。该候选人通过获得流行病学硕士学位和迄今为止专注于艾滋病毒相关心血管疾病领域的研究项目概况，以及改善这一风险的目标，表明了对临床研究事业的奉献精神。该职业发展奖将为候选人从事独立的研究事业提供基础，致力于更好地了解与hiv相关的心血管疾病的病理生理学和目标，以减少随后的发病率和死亡率。

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.