TET2-driven Clonal Hematopoiesis Promotes Disease Progression in Rheumatoid Arthritis

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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.