TET2-driven Clonal Hematopoiesis Promotes Disease Progression in Rheumatoid Arthritis

摘要/总结 这个K 01奖是为苏珊·麦克劳克伦博士提供先进的研究培训，保护时间， 导师需要成为一个独立的研究人员致力于定义克隆造血的作用 类风湿性关节炎（RA）的发病机制。 候选人：MacLauchlan博士是Ellen Gravallese博士实验室的博士后助理。 马萨诸塞州大学医学院医学系，流变学系。博士 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 关节炎领域，并产生新的和创新的见解RA的发病机制。 MacLauchlan博士的K 01项目专注于表观遗传调节剂Ten Eleven的作用 RA背景下的转位酶2（TET 2）。RA是一种严重的自身免疫性疾病， 关节的炎症和侵蚀使患者患心血管疾病的风险增加一倍 疾病TET 2先前被MacLauchlan博士和其他人描述为增加 在小鼠模型中，通过增加IL-1 β的加工来治疗心血管疾病。在这项研究中，博士。 MacLauchlan将利用这些数据并将其应用于新的疾病模式。麦克劳克伦博士建议 评估TET 2在炎症、骨侵蚀和内皮细胞功能障碍中的作用， 发生在RA关节炎滑膜的情况下。 指导/培训：MacLauchlan博士将获得RA研究、骨分析方面的临床和研究培训 技术、内皮细胞功能测定和与TET 2功能有关的特定技术。此外，本发明还 她将学习实验室领导技能，以便过渡到自己的独立实验室。她 进展将由她的主要导师Ellen Gravallese博士和她的共同导师Kenneth博士团队指导 沃尔什和约翰·基尼，并得到了她的合作者沈载赫博士和凯瑟琳·马丁博士的进一步支持。 博士MacLauchlan和她的指导团队将特别确保为她提供适当的职业 发展机会，以促进她过渡到独立调查员。在一起，拟议的 研究提案和培训机会将为MacLauchlan博士获得独立的R 01奠定基础 资助并成为探索RA驱动的风险调解前沿的国家认可的领导者 心血管疾病的患者。

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.