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

Syndecan-2 和 CD148 在类风湿关节炎间质性肺疾病中的抗纤维化作用

• 批准号: 10630201
• 负责人: Konstantin Tsoyi
• 金额: $ 13.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630201
• 关键词: Adult; Affect; Animal Model; Antibodies; Apoptosis; Area; Arthritis; Attenuated; Autoimmune; Automobile Driving; Binding; Binding Proteins; Biological; Biology; Bleomycin; Cartilage; Cell Proliferation; Cell surface; Collagen; Complication; Data; Development; Disease; Environment; Epithelial Cells; Experimental Models; Extracellular Matrix; Family; Fibroblasts; Functional disorder; Funding; Future; Goals; Heparan Sulfate Proteoglycan; Hospitals; Human; Immunology; In Vitro; Inflammatory; Inflammatory Arthritis; Interstitial Lung Diseases; Knowledge; Lung; Lung diseases; Mediating; Medicine; Membrane; Mentors; Mentorship; Modeling; Molecular; Molecular Biology; Mus; Myofibroblast; PIK3CG gene; PTPRJ gene; Pathogenesis; Patients; Persons; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Play; Predisposition; Process; Production; Progressive Disease; Property; Protein Tyrosine Phosphatase; Protein-arginine deiminase; Proteins; Proteoglycan; Pulmonary Fibrosis; Radiation; Recombinants; Regulation; Reporting; Research; Research Personnel; Resources; Rheumatoid Arthritis; Role; Scholarship; Scientist; Self Direction; Signal Transduction; Structure of parenchyma of lung; TGFB1 gene; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Translational Research; United States; United States National Institutes of Health; Woman; Work; age related; alveolar epithelium; bone; career; career development; citrullinated protein; collagen antibody induced arthritis; fibroglycan; fibrotic lung disease; immune activation; in vivo; joint destruction; lung development; medical schools; meetings; member; mortality; mouse model; overexpression; post-doctoral training; protein activation; success; therapeutic target; training opportunity

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.

项目摘要/摘要： 该K01提案描述了一项为期五年的研究和培训计划，该计划将有助于博士的过渡。 Konstantin Tsoyi致类风湿关节炎相关的独立学术研究员 肺部病（RA-ELD）。 Tsoyi博士在分子生物学和药理学方面具有很强的背景 完成了免疫学和肺纤维化的博士后训练。 RA是一种系统性炎症障碍 在美国影响约300万人。 ILD是RA最常见的肺并发症 并与死亡率增加有关。 RA-ild发生在大约10％的晚期RA患者中， 还有30％患有早期疾病，其中一半将进展。关于分子机制知之甚少 参与乳腺的发病机理。当前的应用程序努力创建基本的利基和 转化投资以更好地了解成纤维细胞的作用，在RA-ILD的病理生理学中 制定治疗干预措施的最终目标。 候选人先前已经证明了Syndecan-2（SDC2）的抗纤维化特性，一个成员 在辐射诱导的肺纤维化的动物模型中，硫酸乙酰肝素蛋白聚糖家族的含量。这 该提案的总体目的是描述SDC2在使用体内和体外的RA-ild模型中的作用 方法。申请人假设SDC2缺乏会增加对实验肺的敏感性 纤维化在既定的关节炎鼠模型中。此外，SDC2通过 激活CD148（膜结合的蛋白酪氨酸磷酸酶）并减少PI3K/AKT/SP1 肺成纤维细胞中的信号传导和肽基金氨酸脱氨酶-2（PAD2）表达。这一点的意义 研究是，从这项研究中获得的知识将有助于发展未来治疗 患有RA-ILD的患者。 Tsoyi博士将从他的奖学金监督委员会中获得奖学金，该委员会由杰出的委员会组成 具有与该建议的关键领域有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。 Brigham and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了理想的环境。医学系 BWH致力于Tsoyi博士的成功，并假设了100％的保护时间用于活动 在此提案中描述。候选人的导师博士。伊万·罗萨斯（Ivan Rosas）和迈克尔·布伦纳（Michael Brenner）是NIH资助的 间质性肺疾病和类风湿关节炎领域的研究人员和领导者。此应用程序概述 详细的职业发展和培训计划，其中包括拟议的概述研究 在科学会议上，课程工作，自我指导的阅读，半人物和演讲。专业知识和 从该K01获得的知识将使Tsoyi博士获得R01资金来启动独立研究 职业专注于研究参与RA-ILD发展的分子机制。