Vascular smooth muscle cell heterogeneity and disease

项目摘要 血管细胞异质性是一种引人入胜但知之甚少的现象。众多的维管细胞 不同类型的人在病理条件下经历命运转换。这包括正在经历的内皮细胞(ECs) 内皮-间充质转化(EndMT)与巨噬细胞某些典型特征的获得 和平滑肌细胞(SMC)。反过来，SMC也可以获得巨噬细胞样的特征，而骨骼 骨髓来源的单个核细胞在慢性粒细胞白血病部位可表达某些EC和SMC标记 发炎。这些细胞命运的转变与包括动脉粥样硬化在内的各种病理机制有关， 动脉瘤、肺动脉高压和海绵状脑部畸形。虽然这些细胞的存在 命运转换现在已经被广泛接受，对SMC的起源和特征知之甚少 这些命运改变了。我们的初步数据表明，正常SMC的某些亚群特别是 倾向于表型变化，并且主要致病。我们假设有一小部分人 与SMC池扩大相关的心血管疾病的发病机制 而以这些细胞为靶点可能被证明是一种更好、更具体的治疗方法。这是我们的目标 在此应用程序中定义这些细胞群体，确定是什么驱动了它们的致病反应，并开始 通过专门针对这些SMC确定控制心血管疾病的治疗方法 子集。

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.