Vascular smooth muscle cell heterogeneity and disease

血管平滑肌细胞异质性与疾病

• 批准号: 10559596
• 负责人: Michael Simons
• 金额: $ 83.11万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559596
• 关键词: Abdominal Aortic Aneurysm; Adipocytes; Aneurysm; Aorta; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Bone Marrow; Cardiovascular system; Cartilage; Cell Reprogramming; Cells; Characteristics; Chronic; Clonal Expansion; Clone Cells; Coronary artery; Cytometry; Data; Development; Dilatation - action; Disease; Endothelial Cells; Endothelium; Exhibits; Genetic; Genetic Transcription; Goals; Growth; Health; Heterogeneity; Human; Image; Inflammation; Link; Macrophage; Maps; Medial; Mesenchymal; Mesenchymal Stem Cells; Minority; Molecular; Molecular Analysis; Mononuclear; Mus; Myocardial Infarction; Organ Donor; Paint; Pathogenesis; Pathogenicity; Pathologic; Pathology; Peripheral Vascular Diseases; Phenotype; Physiologic Ossification; Population; Process; Proliferating; Pulmonary Hypertension; Reporting; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Stroke; Therapeutic; Thoracic Aortic Aneurysm; Time; Time Series Analysis; Vascular Diseases; Vascular Smooth Muscle; bone; calcification; cell type; cerebral cavernous malformations; fascinate; human disease; mouse model; novel therapeutics; pathogen; pulmonary arterial hypertension; response; single-cell RNA sequencing; stem-like cell; tool

Project Summary Vascular cell heterogeneity is a fascinating but poorly understood phenomenon. Numerous vascular cell types undergo fate transitions under pathological conditions. This includes endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT) and acquiring certain characteristics typical of macrophages and smooth muscle cells (SMCs). SMCs, in turn, can also acquire macrophage-like features while bone marrow-derived mononuclear cells can express certain EC and SMC markers when present at sites of chronic inflammation. These cells fate transitions have been linked to various pathologies including atherosclerosis, aneurysms, pulmonary hypertension and cavernous cerebral malformations. While the existence of these cell fate transitions is now well accepted, little is known about the origin and characteristics of SMCs undergoing these fate changes. Our preliminary data suggest that certain subpopulations of normal SMCs are particularly prone to phenotypic modulation and are predominately pathogenic. We hypothesize that a small subpopulation of normal SMCs is responsible for pathogenesis of CV diseases associated with expansion of the SMC pool and that targeting these cells might prove to be a better and more specific therapeutic approach. It is our goal in this application to define these cell populations, determine what drives their pathogenic responses and begin identifying therapeutic approaches to controlling CV illnesses driven by specifically targeting these SMC subsets.

项目摘要 血管细胞异质性是一个迷人的，但知之甚少的现象。众多维管细胞 类型在病理条件下经历命运转变。这包括内皮细胞（EC）经历 内皮细胞向间质细胞转化（EndMT），并获得巨噬细胞的某些典型特征 和平滑肌细胞（SMC）。SMC，反过来，也可以获得巨噬细胞样的功能，而骨 骨髓来源的单核细胞可以表达某些EC和SMC标记物，当存在于慢性炎症部位时， 炎症这些细胞的命运转变与各种病理学有关，包括动脉粥样硬化， 动脉瘤、肺动脉高压和海绵状脑畸形。虽然这些细胞的存在 命运转换现在被广泛接受，对SMC经历的起源和特征知之甚少 这些命运的改变。我们的初步数据表明，正常SMC的某些亚群特别 倾向于表型调节并且主要是致病性的。我们假设一小群人 正常SMC的增殖是与SMC池扩张相关的CV疾病发病机制的原因 而靶向这些细胞可能被证明是一种更好、更特异的治疗方法。这是我们的目标 在本申请中，为了定义这些细胞群，确定是什么驱动了它们的致病反应，并开始 确定通过特异性靶向这些SMC来控制CV疾病的治疗方法 子集