TET2-driven Clonal Hematopoiesis Promotes Disease Progression in Rheumatoid Arthritis

TET2驱动的克隆造血促进类风湿关节炎疾病进展

基本信息

批准号：
9806231
负责人：
Susan C. MacLauchlan
金额：
$ 2.82万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-12 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9806231
关键词：
Adoptive Transfer Aging Aorta Arthritis Autoimmune Diseases Biological Assay Biology Bone remodeling Cardiovascular Diseases Catabolism Cell Adhesion Molecules Cell fusion Cell physiology Cells Clinical Research Clonal Expansion Data Development Disease Disease Progression Endothelial Cells Endothelium Ensure Environmental Risk Factor Epigenetic Process Etiology Functional disorder Funding Genes Genetic Goals Grant Hematopoiesis Hematopoietic stem cells Homeostasis Human Immune In Vitro Individual Inflammasome Inflammation Inflammation Process Inflammatory Interleukin-1 beta Joints Knock-out Knockout Mice Laboratories Leadership Learning Leukocytes Link Malignant Neoplasms Massachusetts Mediating Medicine Mentored Research Scientist Development Award Mentors Modeling Mosaicism Mus Mutate Mutation Myelogenous Osteoclasts P-Selectin Pathogenesis Pathogenicity Patient risk Permeability Phenotype Physiological Play Research Research Personnel Research Proposals Research Training Rheumatoid Arthritis Rheumatology Risk Role Sampling Serum Severities Site Somatic Mutation Synovial Membrane Techniques Time Training Twin Studies Universities Vascular Diseases bone bone erosion cardiovascular disorder risk career career development cytokine genetic risk factor in vitro Model inhibitor/antagonist innovation insight joint function joint injury loss of function macrophage medical schools mouse model novel osteoclastogenesis outcome forecast patient population progenitor programs protective effect self-renewal skills therapeutic target training opportunity translocase

项目摘要

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.

摘要/总结该 K01 奖项旨在为 Susan MacLauchlan 博士提供先进的研究培训、受保护的时间和成为一名致力于定义克隆造血作用的独立研究人员需要指导类风湿性关节炎（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大学医学院风湿病学系医学系。麦克劳克兰之前的培训为她提供了心血管疾病领域广泛的专业知识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，并对 RA 的发病机制产生新颖和创新的见解。研究：MacLauchlan 博士的 K01 项目重点研究表观遗传调节剂 10-11 的作用 RA 中的易位酶 2 (TET2) 是一种严重使人衰弱的自身免疫性疾病，表现为：关节炎症和糜烂使患者患心血管疾病的风险加倍 MacLauchlan 博士和其他人之前曾描述 TET2 会增加疾病的严重程度。在拟议的研究中，Dr. 麦克劳克兰博士提出，将利用这些数据并将其应用于新的疾病范例。评估 TET2 在炎症、骨侵蚀和内皮细胞中的贡献发生在 RA 的关节炎滑膜背景下。指导/培训：MacLauchlan 博士将获得 RA、骨骼分析研究方面的临床和研究培训技术、内皮细胞功能测定以及与 TET2 功能相关的特定技术。她将学习实验室领导技能，以促进向自己的独立实验室的过渡。进展将由她的主要导师 Ellen Gravallese 博士和她的共同导师 Kenneth 博士指导。沃尔什和约翰·基尼，以及她的合作者 Jae-Hyuck Shim 和凯瑟琳·马丁博士的进一步支持。 MacLauchlan 博士和她的指导团队将特别确保为她提供适当的职业共同提出发展机会，以促进她过渡为独立调查员。研究计划和培训机会将为 MacLauchlan 博士获得独立 R01 奠定基础融资并成为全国公认的处于探索 RA 驱动风险调解前沿的领导者该患者群体患有心血管疾病。