Antibodies to Citrullinated Protein Antigens, CVD and Bone Disease in MESA

MESA 中瓜氨酸蛋白抗原、CVD 和骨病的抗体

基本信息

批准号：
9283594
负责人：
Jan Marie Hughes-Austin
金额：
$ 17.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9283594
关键词：
Abdomen Address Affect Age Ancillary Study Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigens Apoptosis Area Attenuated Autoantibodies Autoantigens Autoimmune Diseases Award Biometry Bone Density Bone Diseases C-reactive protein Calcified California Cardiovascular Diseases Cardiovascular system Cell physiology Chronic Disease Citrulline Clinical Trials Communities Community Trial Complex Coronary artery Coronary heart disease Development Development Plans Disease Doctor of Philosophy EFRAC Elderly Environment Epidemiology Etiology Evaluation Event Family Practice Family member Funding Future General Population Goals Health High Prevalence Immune response Immunology Individual Inflammation Inflammatory Institution Intervention Intervention Studies Knowledge Lead Left Ventricular Mass Link Longevity Measurement Mentored Research Scientist Development Award Mentors Methods Morbidity - disease rate Multi-Ethnic Study of Atherosclerosis National Heart, Lung, and Blood Institute Osteogenesis Osteoporosis Participant Pathologic Pathology Patients Physical therapy Placebos Population Postdoctoral Fellow Pravastatin Prevalence Prevention Preventive Medicine Process Property Prospective cohort study Proteins Randomized Randomized Clinical Trials Research Research Infrastructure Research Personnel Research Project Grants Rheumatoid Arthritis Rheumatology Risk Factors Risk Marker Sampling Scientist Self-Direction Serum Severities Stress System Time Training Training Activity Universities Vascular Diseases Vascular calcification Vertebral column Woman Work X-Ray Computed Tomography austin bone bone loss calcification cardiovascular disorder epidemiology cardiovascular disorder risk career career development citrullinated protein clinical development clinically significant cohort community living design endothelial dysfunction epidemiology study experience high risk improved insight men mortality novel patient population programs public health relevance risk sharing skills treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Career Development Plan Summary Dr. Hughes-Austin is currently an Integrated Cardiovascular Epidemiology postdoctoral fellow in the Department of Family and Preventive Medicine at the University of California, San Diego. Prior training in physical therapy and epidemiology and research experience in cardiovascular and autoimmune disease converge through both the research plan and training activities outlined in this Mentored Research Scientist Development Award. Dr. Hughes-Austin's career objective is to improve health and wellbeing in the general population through applying principles and findings observed in rheumatologic disease patients to the general population. Dr. Hughes-Austin's long-term career goal is to achieve excellence as an independently funded research scientist working in prevention of chronic diseases. Her immediate goals are to gain knowledge and experience in cardiovascular and bone immunology, bone epidemiology, and integrating these complex systems, as well as to develop the skills necessary to design, execute and analyze randomized clinical trials. UCSD is recognized as one of the nation's top academic and research institutions. It provides numerous opportunities for continued training in coursework as well as established infrastructure and programs devoted to supporting young investigators. Capitalizing on the strong institutional environment, Dr. Hughes-Austin has assembled a team of mentors and consultants with expertise in the areas of cardiovascular epidemiology, bone disease epidemiology, immunology, biostatistics, rheumatology, and clinical trials. Her mentors will not only provide tutorials within their respective areas of expertise and guidance throughout the proposed research project, but will also offer opportunities for intellectual interaction and development beyond the academic setting. Research Plan Summary Cardiovascular disease and osteoporosis affect more than one-third of older adults, and the underlying pathology of these two disease processes involves similar mechanisms. They associate, however, inversely with one another, as lower bone mineral density is associated with a higher prevalence and severity of vascular calcification and higher risk of future CVD events, independent of age and other shared risk factors. Antibodies to citrullinated protein antigens (ACPA) are self-directed antibodies to peptidyl citrulline. While citrullinated proteins occur normally, they become antigenic under inflammatory conditions, thus eliciting a self- directed immune response. ACPA have been linked to bone loss and CVD in rheumatoid arthritis patients and select populations without rheumatoid arthritis. Dr. Hughes-Austin and others have shown that ACPA are detectable in normal healthy control individuals as well. Whether ACPA are associated with CVD and bone disease in the general population, however, remains unknown. If so, their measurement may provide new insights into a novel aspect of inflammatory stress and its impact on both CVD and bone disease; diseases which jointly contribute to substantial morbidity and mortality within the non-rheumatoid arthritis general population. In this study, we propose an efficiently designed ancillary study to the NHLBI funded Multi-Ethnic Study of Atherosclerosis (MESA). Among 1968 multi-ethnic, community-dwelling men and women, our objectives are to determine the independent associations of ACPA with (1) subclinical CVD and incident development of clinical CVD events, and (2) bone mineral density within the MESA cohort. In addition, (3) as statins have known anti- inflammatory properties, we will investigate whether statin use may modify ACPA levels in 200 participants from the Pravastatin Inflammation and C - reactive protein Evaluation (PRINCE) Randomized Clinical Trial. In so doing, upon completion of this award, Dr. Hughes-Austin will be fully trained and ready to independently lead her research career. Moreover, the study will establish whether ACPA are indeed independently linked with CVD and bone disease, and will provide important information on whether or not ACPA levels are modifiable by statins. If the hypotheses prove true, this study will lead directly to Dr. Hughes-Austin's design and implementation of an intervention study to determine whether modifying ACPA may benefit CVD and bone disease in the general population.

描述（由适用提供）：职业发展计划摘要Hughes-Austin博士目前是加利福尼亚大学圣地亚哥分校家庭和预防医学系的综合心血管流行病学研究员。在这项指导的研究科学家发展奖中概述的研究计划和培训活动中，心血管和自身免疫性疾病的物理治疗和流行病学和研究经验的先前培训都融合了研究计划和培训活动。休斯·奥斯汀（Hughes-Austin）博士的职业目标是通过将风湿病患者中观察到的原则和发现应用于普通人群，以改善普通人群的健康和福祉。休斯·奥斯汀（Hughes-Austin）博士的长期职业目标是作为一名从事预防慢性疾病的独立研究科学家的卓越成就。她的直接目标是获得心血管和骨骼免疫学，骨骼流行病学以及整合这些复杂系统的知识和经验，以及开发设计，执行和分析随机临床试验所需的技能。 UCSD被公认为是美国顶级学术和研究机构之一。它为继续培训以及既定的基础设施和专门支持年轻调查员的计划提供了许多机会。 Hughes-Austin博士利用强大的机构环境，在心血管流行病学，骨病流行病学，免疫学，生物统计学，风湿病学和临床试验方面组成了一组导师和顾问团队。她的导师不仅将在整个拟议的研究项目中提供各自的专业知识和指导领域的教程，而且还将为超出学术环境以外的智力互动和发展提供机会。研究计划摘要心血管疾病和骨质疏松症影响了三分之一以上的老年人，而这两种疾病过程的潜在病理涉及相似的机制。但是，由于较低的骨矿物质密度与血管计算的患病率和严重程度较高以及未来CVD事件的较高风险，与年龄和其他共享风险因素无关。瓜氨酸蛋白抗原（ACPA）的抗体是对肽基瓜氨酸的自定向抗体。虽然瓜氨酸蛋白正常发生，但它们在炎症条件下会变成抗原，从而引起了自导向的免疫反应。 ACPA与类风湿关节炎患者的骨质流失和CVD有关，并且没有类风湿关节炎的选择人群。休斯·奥斯汀（Hughes-Austin）博士和其他人表明，在正常健康对照组中也可以检测到ACPA。但是，ACPA是否与普通人群中的CVD和骨骼疾病有关，仍然未知。如果是这样，他们的测量可能会为炎症应激的新方面及其对CVD和骨骼疾病的影响提供新的见解。共同导致非rheumatoid关节炎一般人群中的继发性发病率和死亡率的疾病。在这项研究中，我们建议对NHLBI资助的动脉粥样硬化多民族研究（MESA）进行有效设计的辅助研究。在1968年的多种族中，社区居住的男人和女人中，我们的目标是确定ACPA与（1）亚临床CVD的独立关联和临床CVD事件的事件发展，以及（2）梅萨同胞中的骨矿物质密度。此外，（3）他汀类药物具有已知的抗炎特性，我们将研究他汀类药物的使用是否可以从pravastatin炎症和C-反应性蛋白质评估（Prince）随机临床试验中改变200名参与者的ACPA水平。这样一来，休斯 - 奥斯汀博士将接受全面培训，并准备独立领导她的研究职业。此外，该研究将确定ACPA是否确实与CVD和骨骼疾病独立联系，并将提供有关ACPA水平是否可以通过他汀类药物修饰的重要信息。如果假设被证明是正确的，那么这项研究将直接导致休斯 - 奥斯汀博士的设计和实施干预研究，以确定修改ACPA是否会使普通人群中的CVD和骨骼疾病受益。