TET2-driven Clonal Hematopoiesis Promotes Disease Progression in Rheumatoid Arthritis

摘要/摘要 这一K01奖项是为了向Susan MacLauchlan博士提供高级研究培训、保护时间和 辅导需要成为一名独立的研究人员，致力于确定克隆造血的作用 在类风湿关节炎(RA)的发病机制中起重要作用。 候选人：MacLauchlan博士是Ellen Gravallese博士实验室的博士后助理 麻省大学医学院风湿病学部医学系。Dr。 MacLauchlan之前的培训为她提供了心血管疾病领域的广泛专业知识 和克隆性造血。她提出的职业目标是将她在克隆造血方面的专业知识应用于 研究关节炎领域，并对类风湿关节炎的发病机制产生新的和创新的见解。 研究：MacLauchlan博士的K01项目聚焦于表观遗传调节剂Ten-Eleven的作用 转位酶2(TET2)在类风湿关节炎中的作用。类风湿关节炎是一种严重衰弱的自身免疫性疾病，表现为 关节的炎症和侵蚀，使患者患心血管疾病的风险加倍 疾病。MacLauchlan博士和其他人之前曾描述过TET2可以增加 通过增加小鼠模型中IL-1的处理而导致心血管疾病。在这项拟议的研究中，Dr。 麦克劳克伦将利用这些数据，并将它们应用于一种新的疾病范例。麦克劳克伦博士建议 评价TET2在炎症、骨侵蚀和内皮细胞功能障碍中的作用。 发生在类风湿关节炎滑膜的背景下。 指导/培训：MacLauchlan博士将在RA研究、骨骼分析方面获得临床和研究培训 与TET2功能有关的技术、内皮细胞功能分析和具体技术。另外， 她将学习实验室领导技能，以促进过渡到自己的独立实验室。她 进步将由她的主要导师Ellen Gravallese博士和她的联合导师Dr.Kenneth博士指导 沃尔什和约翰·基尼，以及她的合作者辛在赫博士和凯瑟琳·马丁博士的进一步支持。 麦克劳克伦博士和她的指导团队将特别确保为她提供适当的职业生涯 发展机会，以促进她向独立调查员的转变。总而言之，建议的 研究提案和培训机会将为MacLauchlan博士获得独立R01奠定基础 提供资金，并成为探索RA驱动的风险调解的前沿领域的全国公认的领导者 这一患者群体中的心血管疾病。

ABSTRACT/SUMMARY This K01 award is to provide Dr. Susan MacLauchlan with the advanced research training, protected time, and mentoring needed to become an independent researcher committed to defining the role of clonal hematopoiesis in the pathogenesis of rheumatoid arthritis (RA). Candidate: Dr. MacLauchlan is a Postdoctoral Associate in the laboratory of Dr. Ellen Gravallese in the Department of Medicine, Division of Rheumatology at the University of Massachusetts Medical School. Dr. MacLauchlan’s previous training has provided her with extensive expertise in the field of cardiovascular disease and clonal hematopoiesis. Her proposed career goals are to apply her expertise in clonal hematopoiesis to the field of arthritis and to generate novel and innovative insights into the pathogenesis of RA. Research: Dr. MacLauchlan’s K01 project focuses on the role of the epigenetic modulator Ten Eleven Translocase 2 (TET2) in the context of RA. RA is a severely debilitating autoimmune disease manifesting in inflammation and erosions of the articular joints that doubles the patient’s risk of developing cardiovascular disease. TET2 was previously described by Dr. MacLauchlan and others to increase the severity of cardiovascular disease by increasing processing of IL-1ß in mouse models. In the proposed research, Dr. MacLauchlan will leverage these data and apply them to a new disease paradigm. Dr. MacLauchlan proposes to evaluate the contribution of TET2 in the inflammation, bone erosions, and endothelial cell dysfunction that occur in RA in the context of the arthritic synovium. Mentoring/Training: Dr. MacLauchlan will obtain clinical and research training in the study of RA, bone analysis techniques, endothelial cell function assays, and specific techniques pertaining to TET2 function. Additionally, she will learn laboratory leadership skills to facilitate the transition to her own independent laboratory. Her progress will be directed by her primary mentor, Dr. Ellen Gravallese, her team of co-mentors, Drs. Kenneth Walsh and John Keaney, with further support from her collaborators, Drs. Jae-Hyuck Shim and Kathleen Martin. Dr. MacLauchlan and her Mentoring Team will specifically ensure that she is provided with the appropriate career development opportunities to facilitate her transition into an independent investigator. Together, the proposed research proposal and training opportunities will set the stage for Dr. MacLauchlan to obtain independent R01 funding and become a nationally-recognized leader at the cutting-edge of exploring RA-driven risks mediating cardiovascular disease in this patient population.