JAK2V617F, clonal hematopoiesis and atherosclerosis

项目总结/摘要 传统的危险因素，如高胆固醇血症，糖尿病和高血压， 不能完全预测心血管疾病（CAD），表明存在额外的未知风险 因素最近的研究表明，克隆造血的不确定的潜力（CH）作为一个 新的心血管危险因素和老年人动脉粥样硬化的潜在主要驱动因素。CH是 由赋予造血干细胞增殖优势的突变引起，通常 涉及表观遗传修饰物（TET 2、DNTM 3a、ASXL 1）或信号通路（JAK 2）。 了解CH与CAD相关的潜在机制与以下方面高度相关： 精准医学，并有可能导致新的CAD靶向治疗。收购 造血组织中JAK 2的激活突变，以JAK 2 V617 F（JAK 2 VF）为最多 常见，驱动骨髓增生性疾病和CH的发展;在不同的CH中， JAK 2 VF基因变异与CAD风险增加最明显相关。直到最近 未直接评估因果关系。我们最近发表了一项研究， 模型携带真正的人类一样的Jak 2 VF突变，并证明了有效的亲， 造血Jak 2 VF表达的致动脉粥样硬化作用。在这份提案中，我们将遵循 并产生包括造血谱系特异性Jak 2 VF表达的新型小鼠模型 和Jak 2 VF驱动的CH，以探讨Jak 2 VF驱动的动脉粥样硬化的潜在机制。一 对这些机制的深入了解可能会导致新的治疗方法的开发。 管理CH相关CVD风险的方法，将在本提案中进行评估。

Project Summary/Abstract Conventional risk factors such as hypercholesterolemia, diabetes and hypertension are incompletely predictive of cardiovascular disease (CAD), suggesting additional unidentified risk factors. Recent studies have identified clonal hematopoiesis of indeterminate potential (CH) as a new cardiovascular risk factor and a potential major driver of atherosclerosis in the elderly. CH is caused by mutations that endow a proliferative advantage to hematopoietic stem cells, commonly involving epigenetic modifiers (TET2, DNTM3a, ASXL1) or signaling pathways (JAK2). Understanding the mechanisms underlying the association of CH with CAD is highly relevant in precision medicine and has the potential to lead to novel targeted therapies for CAD. Acquired activating mutations of JAK2 in hematopoietic tissues, with JAK2V617F (JAK2VF) as the most common, drive development of myeloproliferative disorders and CH; amongst the different CH genetic variants JAK2VF is most clearly associated with increased risk of CAD. Until recently the causal relationship had not been directly assessed. We published a study recently using a mouse model carrying the authentic human like Jak2VF mutation and demonstrated potent pro- atherogenic effects of hematopoietic Jak2VF expression. In this proposal, we will follow the leads and generate novel mouse models including hematopoietic lineage specific Jak2VF expression and Jak2VF-driven CH to explore the mechanisms underlying Jak2VF-driven atherosclerosis. A deeper understanding of these mechanisms may lead to development of new therapeutic approaches to managing CH-associated CVD risks, as will be evaluated in this proposal.