Defining the cellular and molecular mechanisms driving neointimal lesion growth in pulmonary hypertension

项目摘要/摘要 肺动脉高压(PH)是一种致命的肺动脉疾病，很少有人支持 接受治疗，却无法治愈。在PH中，闭塞的“新的内膜病变”在小肺内生长。 动脉和狭窄的管腔，最终增加肺血管阻力 导致右心衰竭和死亡。可用的PH疗法是不起作用的血管扩张剂 靶向新生内膜生长，既不能预防疾病进展，也不能逆转疾病。理解 新生内膜病变生长的生物学--哪些细胞负责病变扩张，以及 控制其扩散的途径-是发展更有效的 治疗肺动脉高压的方法。在初步研究中，我们发现增殖的新生内膜 细胞与动脉内皮细胞相邻，具有区别于动脉内皮细胞的独特基因表达 它们来自远离内皮的细胞。我们假设一个分子定义的 位于内皮附近的新生内膜细胞的亚群是增殖部分， 扩大新生内膜病变，内皮细胞信号调节病变生长。 具体目标：(1)利用增殖跟踪、遗传谱系跟踪和消融，确定和 对新生内膜细胞亚群的分子表征，其增殖是导致 病变在增长。(2)通过生物信息学分析新生内膜和血管内皮细胞的单细胞转录 来自小鼠和人的动脉内皮细胞，识别驱动新生内膜的候选信号 PH中的增殖和鼠与人共有的核心疾病机制。(3) 检测新生内膜增殖的关键候选驱动因素在病变生长中的作用 多种PH型号。在这里，通过利用尖端技术、遗传学和单细胞 跨多个模型系统的方法，这些实验将提供细粒度 了解推动新生内膜病变扩张的细胞和信号，实质上增加了 根据目前围绕PH血管重塑病理的认识，我们的发现 希望最终将导致新的血管内膜阻断治疗选择。

Project Summary/Abstract Pulmonary hypertension (PH) is a fatal disease of the pulmonary arteries with few supportive therapies and no cure. In PH, occlusive `neointimal lesions' grow within small pulmonary arteries and narrow vessel lumens, increasing pulmonary vascular resistance, ultimately resulting in right heart failure and death. Available PH therapies are vasodilators that do not target neointimal growth and neither prevent progression nor reverse disease. Understanding the biology of neointimal lesion growth – which cells are responsible for lesion expansion, and the pathways that control their proliferation – is key to the development of more effective therapies for pulmonary hypertension. In preliminary studies we find that proliferating neointima cells are adjacent to artery endothelial cells and have distinct gene expression that distinguishes them from cells located away from the endothelium. We hypothesize that a molecularly defined subset of neointimal cells located adjacent to the endothelium is the proliferating fraction that expands neointimal lesions, and that signals from the endothelium regulate lesion growth. Specific Aims: (1) Using proliferation tracking, genetic lineage tracing and ablation, identify and molecularly characterize the subset of neointimal cells whose proliferation is responsible for lesion growth. (2) Through bioinformatic analysis of single cell transcription in neointima and artery endothelial cells from mouse and human, identify candidate signals driving neointimal proliferation in PH and the core disease mechanisms shared between mouse and human. (3) Test the ability of a key candidate driver of neointimal proliferation for a role in lesion growth in multiple PH models. Here, by utilizing cutting edge technologies, genetics, and single cell approaches across multiple model systems, these experiments will provide a granular understanding of the cells and signals driving neointimal lesion expansion, adding substantially to the current knowledge surrounding the pathology of vascular remodeling in PH, findings we hope will ultimately lead to neointima-blocking treatment options.