Studies of Autoimmunity and Atherosclerosis

描述（由申请人提供）：心血管疾病（CVD）仍然是美国死亡的主要原因。三分之一的美国人患有心血管疾病，每年有91万人死于心血管疾病。结缔组织疾病（CTD）已被确定为冠状动脉疾病（CAD）的危险因素。类风湿性关节炎和狼疮等CTDs患者的CAD患病率很高，而且发病年龄比预期的要小。有人提出CTDs和CAD之间的关联与炎症有关。此外，动脉粥样硬化中已发现循环自身抗体，因此动脉粥样硬化可能具有自身免疫特征。无症状个体中自身抗体的存在是未来临床CTD的预测因子。虽然CTD和CAD之间的联系已经确立，但临床前自身免疫和CVD之间的联系尚未探讨。我是一名风湿病学家/内科医生，其目标是发展独立的临床研究事业，重点是识别心血管疾病发病率的临床前自身免疫标志物。拟议的职业发展计划包括一个密集的指导，以病人为导向的研究经验与硕士学位课程相结合。我将与我的导师一起开展研究CVD自身免疫危险因素的项目：1)我将在年轻人（CARDIA）和中年人（MESA）两个前瞻性队列中进行辅助研究，以研究心脏风险的发展。我将在研究CARDIA受试者和MESA受试者的临床前自身免疫与亚临床动脉粥样硬化之间的关系时，获得研究设计和数据收集方面的经验。2)我将研究临床前自身免疫与传统心血管疾病危险因素演变之间的关系。3)我将在R01申请中使用这些初步数据，建议利用整个MESA队列进一步阐明介导自身免疫与CVD之间关联的机制。相关性：本文提出的研究为心脏风险研究提供了创新。大样本量和自身抗体的广泛评估将使我们能够解决自身免疫是亚临床动脉粥样硬化的危险因素这一独特假设。如果事实上，自身免疫被发现与动脉粥样硬化独立相关，那么从本研究中获得的信息可能在未来用于识别CAD的相关危险因素，从而可以实施一级和二级预防措施。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) remains the leading cause of death in the USA. One in 3 Americans develop CVD and 910,000 die from CVD annually. Connective tissue diseases (CTD) have been identified as risk factors for coronary artery disease (CAD). Patients with CTDs such as rheumatoid arthritis and lupus have a high prevalence of CAD and are younger than expected at CAD onset. It has been proposed that the association between CTDs and CAD is related to inflammation. Furthermore, circulating autoantibodies have been identified in atherosclerosis, thus atherosclerosis may have autoimmune features. The presence of autoantibodies in asymptomatic individuals is a predictor of future clinical CTD. Although the association between CTD and CAD is established, an association between pre-clinical autoimmunity and CVD has not been explored. I am a rheumatologist/internist whose goal is to develop an independent clinical research career with a focus on the identification of pre-clinical autoimmune markers for the incidence of CVD. The proposed career development plan incorporates an intensive mentored, patient-oriented research experience in combination with a Master's Degree curriculum. I will work with my mentors to conduct projects examining autoimmune risk factors for CVD: 1) I will conduct ancillary studies in two prospective cohorts following young adults (CARDIA) and middle aged adults (MESA) for development of cardiac risk. I will gain hands on experience in study design and data collection as I examine the association between pre-clinical autoimmunity and sub-clinical atherosclerosis in the CARDIA subjects and a subset of the MESA subjects. 2) I will examine the associations between pre-clinical autoimmunity and evolution of traditional CVD risk factors. 3) I will use these preliminary data in an R01 application proposing to utilize the entire MESA cohort to further elucidate the mechanisms that mediate the association between autoimmunity and CVD. Relevance: The studies proposed here offer innovation to the study of cardiac risk. The large sample size and the extensive evaluation of autoantibodies will allow us to address the unique hypothesis that autoimmunity is a risk factor for sub-clinical atherosclerosis. If in fact, autoimmunity is found to be independently associated with atherosclerosis, then information gained from this study may be used in the future to identify pertinent risk factors for CAD so that primary and secondary prevention measures can be implemented.