Antifibrotic effects of Syndecan-2 and CD148 in Rheumatoid Arthritis Interstitial Lung Disease

项目概要/摘要： 这份K 01提案描述了一个五年研究和培训计划，将促进博士的过渡。 Konstantin Tsoyi是类风湿性关节炎相关间质性疾病领域的独立学术研究人员。 肺疾病（RA-ILD）。Tsoyi博士在分子生物学和药理学方面有很强的背景， 完成了免疫学和肺纤维化的博士后培训。类风湿关节炎是一种全身性炎症性疾病 影响了美国约300万人。ILD是RA最常见的肺部并发症 并与死亡率增加有关。大约10%的晚期RA患者发生RA-ILD， 还有30%的人患有早期疾病，其中一半会继续发展。关于其分子机制知之甚少 参与RA- ILD的发病机制。目前的应用程序努力创造一个利基的基本和 翻译研究，以更好地了解成纤维细胞在RA-ILD病理生理学中的作用， 最终目标是开发治疗性干预措施。 候选人先前已经证明了syndecan-2（SDC 2）的抗纤维化特性， 硫酸乙酰肝素蛋白聚糖家族的蛋白聚糖在放射诱导的肺纤维化动物模型中的作用。的 本提案的总体目标是使用体内和体外方法描述SDC 2在RA-ILD模型中的作用 接近。申请人假设SDC 2缺乏增加了对实验性肺损伤的易感性。 在建立的关节炎小鼠模型中观察到纤维化。此外，SDC 2通过以下途径发挥抗纤维化作用： 激活CD 148（一种膜结合蛋白酪氨酸磷酸酶）并降低PI 3 K/Akt/Sp1 信号传导和肽基精氨酸脱亚胺酶-2（PAD 2）在肺成纤维细胞中的表达。其意义 这项研究所获得的知识将有助于开发未来的治疗方法， 患有RA-ILD的患者。 Tsoyi博士将接受他的奖学金监督委员会的指导，该委员会由杰出的 与该提案的关键领域相关的专业知识的科学家，包括肺纤维化，RA和成纤维细胞生物学。 布里格姆妇女医院（BWH）和哈佛医学院的培训机会和资源 (HMS)为候选人的职业发展提供理想的环境。医学系 BWH致力于Tsoyi博士的成功，并保证100%保护时间用于活动 在这个提案中描述。候选人的导师，伊万罗萨斯和迈克尔布伦纳博士，是NIH资助的 间质性肺病和类风湿性关节炎领域的研究者和领导者。该应用程序概述了 一份详细的职业发展和培训计划，其中包括建议的指导研究，教学 课程作业，自我指导的阅读，研讨会，并在科学会议上演示。的专门知识和 从K 01获得的知识将使Tsoyi博士能够获得R 01资金，以启动一项独立的研究 职业生涯专注于研究参与RA-ILD发展的分子机制。

Project Summary/Abstract: This K01 proposal describes a five-year research and training plan that will facilitate the transition of Dr. Konstantin Tsoyi to an independent academic researcher in the field of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Dr. Tsoyi has a strong background in molecular biology and pharmacology and has completed post-doctoral training in immunology and lung fibrosis. RA is a systemic inflammatory disorder affecting approximately 3 million people in the United States. ILD is the most common lung complication of RA and is associated with increased mortality. RA-ILD occurs in approximately 10% of patients with advanced RA, and another 30% with early disease, half of whom will progress. Little is known about the molecular mechanisms involved in the pathogenesis of RA- ILD. The current application endeavors to create a niche of basic and translational investigation to better understand the role of fibroblasts, in the pathophysiology of RA-ILD with the ultimate goal of developing therapeutic interventions. The candidate has previously demonstrated the antifibrotic properties of syndecan-2 (SDC2), a member of the heparan sulfate proteoglycan family, in an animal model of radiation-induced pulmonary fibrosis. The overarching aim of this proposal is to delineate the role of SDC2 in a model of RA-ILD using in vivo and in vitro approaches. The applicant hypothesizes that SDC2 deficiency increases susceptibility to experimental lung fibrosis in an established arthritis murine model. Furthermore, SDC2 exerts antifibrotic effects by activating CD148 (a membrane-bound protein tyrosine phosphatase) and reducing PI3K/Akt/Sp1 signaling and peptidylarginine deiminase-2 (PAD2) expression in lung fibroblasts. The significance of this research is that knowledge gained from this study will contribute to the development of future therapeutics for patients affected with RA-ILD. Dr. Tsoyi will receive mentorship from his scholarship oversight committee, composed of distinguished scientists with expertise related to key areas of this proposal, including lung fibrosis, RA and fibroblast biology. The training opportunities and resources at Brigham and Women’s Hospital (BWH) and Harvard Medical School (HMS) provide an ideal environment for the candidate’s career development. The Department of Medicine at BWH is committed to Dr. Tsoyi’s success and has assured 100% protected time to devote to the activities described in this proposal. The candidate’s mentors, Drs. Ivan Rosas and Michael Brenner, are NIH-funded investigators and leaders in the fields of interstitial lung disease and rheumatoid arthritis. This application outlines a detailed career development and training plan that includes the proposed mentored research, didactic coursework, self-directed readings, seminars, and presentations at scientific meetings. The expertise and knowledge gained from this K01 will enable Dr. Tsoyi to obtain R01 funding to launch an independent research career focused on the study of molecular mechanisms involved in the development of RA-ILD.