Investigating the Pathological Features of Clonal Hematopoiesis-derived Macrophages

研究克隆性造血源性巨噬细胞的病理特征

• 批准号: 10571348
• 负责人: Shaneice R. Mitchell
• 金额: $ 15.57万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571348
• 关键词: Acceleration; Address; Age; Aging; Alleles; Antibodies; Atherosclerosis; Benign; Biological Assay; Bone Marrow Cells; CD34 gene; Cardiovascular Diseases; Cause of Death; Cells; Chronic; Clinical; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; DNMT3a; Development; Disease; Elderly; Engineering; Epigenetic Process; Exposure to; Gene Expression Profile; General Population; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Heart Diseases; Heart failure; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Hypertension; Imaging technology; Immunodeficient Mouse; Individual; Inflammation; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Leukocytes; Link; Lipopolysaccharides; Low-Density Lipoproteins; Macrophage; Measures; Mediating; Mentors; Minority Participation; Modeling; Multiplexed Ion Beam Imaging; Mus; Mutate; Mutation; Myeloid Cells; Myocardial Infarction; Nature; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmacologic Substance; Phase; Phenotype; Physiology; Population; Prevalence; Production; Protein Isoforms; Protocols documentation; Public Health; Receptor Gene; Reporting; Research Personnel; Risk; Risk Factors; Role; Science; Signal Pathway; Stroke; Surface; System; Transgenic Mice; Transplantation; Variant; Work; age related; atherosclerosis risk; cytokine; engineered stem cells; hematopoietic stem cell expansion; high risk; human model; humanized mouse; hypercholesterolemia; in vivo; in vivo engraftment; insight; interest; leukemia; loss of function mutation; mortality; mouse model; pharmacologic; protective effect; transcriptome sequencing; transcriptomics

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.

项目总结 不确定潜能克隆性造血(CHIP)是一种年龄相关的疾病，由扩张性疾病定义 在没有血液学的情况下，含有白血病中常见突变的造血细胞 恶性肿瘤或相关的病理。芯片在老龄化社区中非常普遍，约有10%-30% 70岁以上的人患上这种疾病，并与以下人群的死亡率增加有关 老年人。令人惊讶的是，死亡率的增加在很大程度上是由动脉粥样硬化风险的增加推动的。 心血管疾病(ASCVD)。芯片携带者患心肌梗死的风险增加了2倍 脑梗塞、中风和心力衰竭。小鼠研究表明CHIP与ASCVD之间存在因果关系，主要是 通过上调致病巨噬细胞的促炎途径。尽管鼠标模型的使用 使我们能够洞察到涉及芯片的重要机制，人类生理方面 它们不是在老鼠系统中捕捉到的。这项研究将利用一种易处理的、人类初级功能模型 用人源化小鼠模型研究CHIP相关的病理特征 动脉硬化。 这项拟议的研究的目的是确定人类细胞中的哪些机制在芯片- 相关ASCVD。这项研究的总体假设是，与芯片相关的突变将增加关键的炎症反应 人类髓系细胞中可能不一定在小鼠中保守的信号通路，有助于 心血管疾病的恶化。本提案涉及的目标是：1)确定 原代人巨噬细胞在促炎激活下的转录变化，2)确定 IL-6R突变体对原代人CHIP相关CVD保护作用机制的研究 巨噬细胞，以及3)确定巨噬细胞在慢性炎症模型中的表型变化。 人源化小鼠体内系统中的克隆性造血。人巨噬细胞原代模型的应用 芯片将弥合临床观察到的知识与已有的知识之间的差距 在CHIP的小鼠模型中观察到。这项提案的工作可能会为药物提供合适的靶标 干预。