HDL Function as a Biomarker for Atherosclerotic Risk in Rheumatoid Arthritis

描述(由申请者提供)：本建议书描述了一项为期5年的风湿病学术生涯发展培训计划。这位首席研究员已经完成了加州大学洛杉矶分校(UCLA)风湿学的正式奖学金培训，目前正在完成临床研究方法学硕士学位的工作。这一独特的跨学科培训计划将以候选人的临床科学背景为基础，扩大她在实验室研究、生物统计学和流行病学领域的技能，以便成功地发展为一名独立的翻译研究人员。加州大学洛杉矶分校生物标记物发现中心联席主任、动脉粥样硬化和脂蛋白研究领域公认的领导者斯里尼瓦萨·T·雷迪博士和加州大学洛杉矶分校风湿病临床试验中心主任、临床调查专家丹尼尔·E·弗斯特博士将共同指导首席研究员的科学发展。研究将集中在类风湿性关节炎(RA)患者的炎症和过早动脉粥样硬化中脂蛋白的功能作用。雷迪博士实验室的研究表明，与标准的高密度脂蛋白胆固醇水平相比，高密度脂蛋白功能的抗炎或促炎特性是动脉粥样硬化更敏感的指标。异常的促炎性高密度脂蛋白在类风湿性关节炎患者中比健康对照组更常见，候选人最近的工作表明，它与疾病严重性、活动性和高密度脂蛋白中结合珠蛋白的增加有关。具体目的包括：1)通过检测240例RA患者的颈动脉内膜厚度和斑块，确定异常的高密度脂蛋白抗炎功能是否导致RA患者动脉粥样硬化的增加。2)确定高密度脂蛋白的特定蛋白质组分是否与a)高密度脂蛋白功能异常、b)动脉粥样硬化和c)类风湿关节炎的疾病活动性有关。3)确定RA疾病活动对横断面RA队列中高密度脂蛋白功能和高密度脂蛋白相关蛋白的累积影响。相关性(参见说明^：识别指示RA患者早期动脉粥样硬化机制的生物标记物是预防该人群心血管疾病(CVD)发病率的重要步骤。高密度脂蛋白功能障碍的特征可能会加深我们对RA患者患心血管疾病风险增加的理解，也可能指导我们开发新的策略，显著影响心血管疾病的发病率和死亡率。 (摘要结束)

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)