Studies of Autoimmunity and Atherosclerosis

简介(申请人提供)：心血管疾病(CVD)仍然是美国主要的死亡原因。每三个美国人中就有一个患上心血管疾病，每年有91万人死于心血管疾病。结缔组织病(CTD)被认为是冠状动脉疾病(CAD)的危险因素。患有CTD的患者，如类风湿性关节炎和狼疮，冠心病的患病率很高，而且发病时比预期的要年轻。已有研究表明，CTDS与CAD之间的关系与炎症有关。此外，在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的预测指标。虽然CTD和CAD之间的联系已经建立，但临床前自身免疫和CVD之间的联系还没有被探索。我是一名风湿学家/内科医生，我的目标是发展独立的临床研究生涯，专注于识别心血管疾病发病率的临床前自身免疫标记物。拟议的职业发展计划将强化指导、以患者为导向的研究经验与硕士学位课程相结合。我将与我的导师合作开展研究心血管疾病自身免疫风险因素的项目：1)我将在两个前瞻性队列中进行辅助研究，研究对象分别是年轻人(CARDIA)和中年人(MESA)，研究对象是心脏病风险的发生。当我在CARDIA受试者和MESA受试者中研究临床前自身免疫和亚临床动脉粥样硬化之间的联系时，我将在研究设计和数据收集方面获得实践经验。2)我将研究临床前自身免疫与传统心血管危险因素演变之间的关系。3)我将在R01应用中使用这些初步数据，建议利用整个MESA队列进一步阐明调节自身免疫和心血管疾病之间关联的机制。相关性：这里提出的研究为心脏风险的研究提供了创新。大样本量和对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。事实上，如果发现自身免疫与动脉粥样硬化独立相关，那么从这项研究中获得的信息可能在未来被用来识别与CAD相关的危险因素，以便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.