HDL Function as a Biomarker for Atherosclerotic Risk in Rheumatoid Arthritis

描述（由申请人提供）：此提案描述了风湿病学学术生涯发展的5年培训计划。首席研究员已经在加州大学洛杉矶分校（UCLA）完成了风湿病学的正式奖学金培训，目前正在完成临床研究方法学的硕士学位。这个独特的跨学科培训项目将建立在候选人的临床科学背景上，扩展她在实验室研究、生物统计学和流行病学领域的技能，以便成功发展成为一名独立的转化研究人员。Srinivasa T. Reddy博士是加州大学洛杉矶分校生物标志物发现中心的联合主任，也是动脉粥样硬化和脂蛋白研究领域公认的领导者，Daniel E. Furst博士是加州大学洛杉矶分校风湿病临床试验中心的主任，也是临床研究方面的专家，他们将共同指导首席研究员的科学发展。研究将集中在脂蛋白在类风湿关节炎（RA）患者炎症和过早动脉粥样硬化中的功能作用。Reddy博士实验室的研究表明，与标准HDL胆固醇水平相比，HDL功能的抗炎或促炎性质是动脉粥样硬化更敏感的指标。异常的促炎性HDL在RA患者中比健康对照组更常见，候选人最近的研究表明，它与疾病严重程度、活动性和HDL中接触珠蛋白升高有关。具体目的包括：1)在240例RA患者中，通过检测HDL抗炎功能异常与颈动脉内膜壁厚度和斑块的关系，确定其是否与RA患者动脉粥样硬化增加有关。2)确定HDL的特定蛋白质成分是否与a) HDL功能异常、b)动脉粥样硬化和c) RA的疾病活动性相关。3)在横断面RA队列随访3年，确定RA疾病活动性对HDL功能和HDL相关蛋白的累积影响。相关性(见说明书^：识别类风湿关节炎患者早期动脉粥样硬化机制的生物标志物是预防该人群心血管疾病（CVD）发病率的重要一步。HDL功能障碍的特征可以进一步理解RA患者患CVD风险增加的原因，也可以指导我们制定新的策略来显著影响心血管发病率和死亡率。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in rheumatology. The principal investigator has completed formal fellowship training in rheumatology at the University of California in Los Angeles (UCLA) and is currently finishing work for a master's degree in clinical research methodology. This unique, interdisciplinary training program will build upon the candidate's clinical science background, expanding her skills in areas of laboratory research, biostatistics, and epidemiology in order for successful development as an independent translational researcher. Dr. Srinivasa T. Reddy, co-director of the Center for Biomarker Discovery at UCLA and a recognized leader in atherosclerosis and lipoprotein research, and Dr. Daniel E. Furst, director of the Rheumatology Clinical Trials Center at UCLA and an expert in clinical investigation, will co-mentor the principal investigator's scientific development. Research will focus on the functional role of lipoproteins in inflammation and premature atherosclerosis in patients with rheumatoid arthritis (RA). Work in Dr. Reddy's lab has suggested that the anti- or pro-inflammatory nature of HDL function is a more sensitive indicator of atherosclerosis than standard HDL cholesterol levels. Abnormal, pro-inflammatory HDL is more common in RA patients than healthy controls and recent work by the candidate suggests that it is associated with increased disease severity, activity, and increased haptoglobin in HDL. Specific aims include: 1) To determine whether abnormal HDL anti-inflammatory function contributes to Increased atherosclerosis in patients with RA by examining its association with carotid intima wall thickness and plaque in a cohort of 240 RA patients. 2)To determine whether specific protein components of HDL are associated with a) abnormal HDL function, b) atherosclerosis, and c) disease activity in RA. 3) To determine the cumulative effects of RA disease activity on HDL function and HDL-associated proteins in a cross sectional RA cohort followed for three years. RELEVANCE (See instructions^: Identification of biomarkers that indicate a mechanism for early atherosclerosis in patients with RA is an important step in preventing morbidity from cardiovascular disease (CVD) in this population. Characterization of HDL dysfunction may further our understanding of why RA patients are at increased risk for CVD, and may also guide us in the development of new strategies to significantly impact CV morbidity and mortality. (End of Abstract)