Investigating the Pathological Features of Clonal Hematopoiesis-derived Macrophages

项目摘要 不确定潜能的克隆性造血（CHIP）是一种与年龄相关的疾病， 在缺乏血液学检查的情况下， 恶性肿瘤或相关病理。CHIP在老龄化社区中非常普遍，约有10-30%的 70岁以上的人获得条件，并与死亡率增加， 老人令人惊讶的是，这种死亡率的增加主要是由动脉粥样硬化的风险升高引起的。 心血管疾病（ASCVD）。CHIP携带者被发现有2倍增加的心肌梗死风险。 梗塞中风和心力衰竭小鼠研究表明，CHIP与ASCVD之间存在因果关系， 通过上调致病性巨噬细胞中的促炎途径。尽管小鼠模型的使用 使我们能够深入了解涉及CHIP的重要机制，人类生理学的某些方面 在鼠系统中没有被捕获。这项研究将利用一个易于处理的，人类主要的功能模型， CHIP巨噬细胞，沿着人源化小鼠模型，研究CHIP相关的病理特征 动脉粥样硬化 这项研究的目的是确定人类细胞中的哪些机制在CHIP中是重要的。 ASCVD相关这项研究的总体假设是，CHIP相关的突变将增加关键的炎症反应。 人骨髓细胞中的信号通路在小鼠中可能不一定保守， 心血管疾病恶化。本建议的目的是：1）确定 在促炎活化下原代人巨噬细胞的转录变化，2）以确定 IL-6受体变异体对CHIP相关CVD的保护作用的机制 巨噬细胞，和3）确定巨噬细胞在慢性炎症模型中的表型变化。 人源化鼠体内系统中的克隆造血。使用原代人巨噬细胞模型， CHIP将弥合临床观察结果与实际情况之间的知识差距 在CHIP的鼠模型中观察到。这项提案的工作可能会为制药业提供合适的目标。 干预

PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition defined by the expansion of hematopoietic cells that harbor mutations commonly found in leukemia, in the absence of hematological malignancies or related pathologies. CHIP is highly prevalent in the aging community, with about 10-30% of individuals over the age of 70 acquiring the condition, and is associated with an increased mortality rate among the elderly. Surprisingly, this increased mortality rate is largely driven by an elevated risk of atherosclerotic cardiovascular disease (ASCVD). CHIP carriers have been found to have a 2-fold increased risk of myocardial infarction, stroke, and heart failure. Murine studies have shown a causal association of CHIP with ASCVD, largely by upregulating proinflammatory pathways in pathogenic macrophages. Though the use of mouse models has allowed us to gain insight into important mechanisms involving CHIP, there are aspects of human physiology that are not captured in a murine system. This study will utilize a tractable, human primary model of functional CHIP macrophages, along with humanized mouse models to study the pathological features of CHIP-related atherosclerosis. The objective of this proposed study is to determine what mechanisms in human cells are important in CHIP- related ASCVD. The overall hypothesis of this study is that CHIP-related mutations will increase key inflammatory signaling pathways in human myeloid cells that may not necessarily be conserved in mice, contributing to exacerbation of cardiovascular disease. The aims addressed in this proposal are: 1) to determine the transcriptional changes in primary human macrophages under proinflammatory activation, 2) to determine the mechanisms mediating the protective effect of an IL6R variant for CHIP associated CVD in primary human macrophages, and 3) to determine phenotypic changes of macrophages in a chronic inflammation model of clonal hematopoiesis in a humanized murine in vivo system. The use of a primary human macrophage model of CHIP will bridge the gap in knowledge between what has been observed clinically versus what has been observed in murine models of CHIP. Work for this proposal may suggest suitable targets for pharmaceutical intervention.