Clinical and Molecular Characteristics of Rheumatoid Arthritis-associated ILD

 描述(申请人提供)：研究类风湿性关节炎(RA)是一种全身性炎症性疾病，在美国大约有130万人受到影响。间隙 肺病(ILD)是类风湿性关节炎(RA)常见的肺部并发症，发病率和死亡率呈上升趋势。虽然RA相关性ILD与其他类型的肺纤维化相似，众所周知，这些类型的肺纤维化会增加呼吸道症状和功能减退，但对RA相关性ILD的特征和自然病史知之甚少。一些研究表明，存在一种与RA相关的ILD谱，大约10%的RA患者患有晚期疾病，另有30%的患者患有早期疾病，其中一半将会进展。吸烟者的早期ILD与呼吸道症状轻度增加、总肺活量减少和功能减退有关；然而，这些发现在RA人群中还没有得到很好的表征。研究还表明，将外周血分子标志物添加到这些临床参数中，可能会增强对纤维化肺疾病患者的评估和预测。在这份职业发展建议书中，申请人假设与RA相关的ILD将与一系列放射学变化、功能减退、呼吸道症状和外周血液分子标志物相关。她建议根据这些功能和分子特征创建一个临床预测分数，以提高对患有早期和晚期疾病的受试者的识别。具体地说，在她的第一个目标中，她将探索早期和晚期与RA相关的ILD与功能减退之间的关系，如肺功能测试和6分钟步行距离，以及呼吸道症状。在她的第二个目标中，她将确定与RA相关的ILD相关的外周血液分子标记物，并将这些标记物与功能损害的程度相关联。在她的第三个目标中，她将建立一个临床预测分数，并在一个独立的队列中验证这个分数。为了实现这一建议的目标，将开发一组具有良好特征的早期和晚期ILD的RA患者队列，为未来的纵向研究提供宝贵的资源。这项研究的成功完成将为我们提供新的非侵入性方法来识别RA相关ILD的风险，并更好地了解RA相关ILD的特征和自然历史。这将使对受影响的个人进行更密切的监测和更早的治疗，有可能降低与RA相关的ILD患者的发病率和死亡率。候选人申请者的长期职业目标是成为一名独立的临床/转化性NIH资助的研究员，专注于以患者为导向的肺部研究。为了实现这一目标，她的短期职业目标是获得完成拟议研究所需的临床研究、定量和分析技能，并成为一名独立的、以患者为导向的研究人员。此外，申请者将获得必要的临床和科学专业知识和出版记录，以确定自己是风湿性关节炎(RA)患者间质性肺病(ILD)领域的权威。这将通过一个职业发展计划来实现，该计划将正式的教学学，包括高级流行病学、生物统计学、生物标记物和编程课程，与会议出席、临床活动以及由导师、顾问和合作者组成的多学科团队的指导和支持相结合。通过她的研究经验和职业发展计划获得的独特的技能和科学知识的结合，以及它们在RA相关ILD领域的应用，将帮助她建立独立于她的指导团队，并为实现她的长期职业目标做好准备。环境申请人将在一家世界知名的主要学术机构进行她建议的研究和职业发展/培训活动。她将工作的部门是一个丰富的研究环境，在导师、学术领导和智力互动方面有着出色的历史。该机构对申请者的成功职业发展非常投入，包括为她的职业发展和她的申请中提出的研究提供所有必要的设施、资源和设备。此外，她将完全有机会接触到一个强大和特征良好的类风湿性关节炎患者队列，以及与多个地方和国家机构的合作安排。这一点，再加上她经验丰富的导师和在与她的研究直接相关的领域拥有专业知识的多学科咨询委员会，确保了她提出的研究和她职业发展计划的目标是合理、适当和可行的。

 DESCRIPTION (provided by applicant): Research Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million people in the United States. Interstitial lung disease (ILD) is a common lung complication of RA with increasing prevalence and mortality. Although RA-associated ILD is similar to other types of lung fibrosis, which are well known to have increased respiratory symptoms and functional decrements, little is known about the characteristics and natural history of RA-associated ILD. Some studies have suggested that there is a spectrum of RA-associated ILD with approximately 10% of RA patients having advanced disease, and another 30% with early disease, half of whom will progress. Early ILD in smokers has been associated with mildly increased respiratory symptoms, reduced total lung capacity, and functional decrements; however these findings have not been well characterized in an RA population. It has also been shown that the addition of peripheral blood molecular markers to such clinical parameters may enhance the assessment and prognostication of individuals with fibrotic lung diseases. In this career development proposal, the applicant hypothesizes that RA-associated ILD will be associated with a spectrum of radiologic changes, functional decrements, respiratory symptoms, and peripheral blood molecular markers. She proposes to create a clinical prediction score from these functional and molecular characteristics to improve the identification of subjects with both early and advanced disease. Specifically, in her first aim, she will explore the relationship between early and advance RA-associated ILD with respect to functional decrements, as measured by lung function testing and the distance walked in six minutes, and respiratory symptoms. In her second aim, she will identify peripheral blood molecular markers that are associated with RA-associated ILD, and correlate those markers with the degree of functional impairment. In her third aim, she will build a clinical prediction score and validate this score in an independent cohort. To achieve the aims of this proposal, a cohort of well-characterized RA patients with early and advanced ILD will be developed, providing an invaluable resource for future longitudinal studies. The successful completion of this research will provide us with novel non-invasive ways to identify those at risk for RA-associated ILD as well as a better understanding of the characteristics and natural history of RA- associated ILD. This will enable closer monitoring and earlier treatment of affected individuals, potentially leading to decreased morbidity and mortality in individuals afflicted with RA-associated ILD. Candidate The applicant's long-term career goal is to become an independent clinical/translational NIH funded investigator focused on patient-oriented pulmonary research. In order to achieve this goal, her short-term career objectives are to acquire the clinical research, quantitative, and analytical skills necessary to complete the proposed research and become an independent patient-oriented researcher. Additionally the applicant will obtain the clinical and scientific expertise and publication record necessary to define herself as an authority in the field of interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This will be accomplished through a career development plan that integrates formal didactics, including advanced epidemiology, biostatistics, biomarker, and programming courses, with conference attendance, clinical activities, and the guidance and support of her multidisciplinary team of mentors, advisors, and collaborators. The unique combination of skills and scientific knowledge gained through her research experience and career development plan and their application to the field of RA-associated ILD will help her to establish independence from her mentorship team and prepare her to achieve her long-term career goal. Environment The applicant will perform her proposed research and career development / training activities at a world- renowned major academic institution. The division in which she will work is a rich research environment with an outstanding history of mentorship, academic leadership, and intellectual interaction. This institution is very invested in the applicant's successful career development, including making available all the facilities, resources, and equipment necessary for her career enhancement and the research proposed in her application. In addition, she will have full access to a robust and well-characterized cohort o rheumatoid arthritis subjects, as well as collaborative arrangements with multiple local and national institutions. This, combined with her accomplished mentors and multidisciplinary advisory committee with expertise in areas directly relevant to her research, ensures that her proposed research and the goals of her career development plan are well-reasoned, appropriate, and feasible.