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

定义驱动肺动脉高压新内膜病变生长的细胞和分子机制

• 批准号: 10594934
• 负责人: Maya Elise Kumar
• 金额: $ 66.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-20 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594934
• 关键词: Ablation; Address; Adult; Affect; Arteries; Automobile Driving; Bioinformatics; Biological Models; Biology; Cell division; Cells; Cessation of life; Child; Consensus; Data; Data Set; Development; Disease; Drug usage; Endothelial Cells; Endothelium; Gene Expression; Gene Expression Profile; Generations; Genetic; Genetic Transcription; Genomics; Growth; Growth and Development function; Human; In Situ; Knowledge; Lesion; Location; Lung; Lung diseases; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; NOTCH3 gene; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Positioning Attribute; Process; Proliferating; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Rattus; Rodent Model; Role; Sampling; Signal Pathway; Signal Transduction; Supportive care; Technology; Testing; Tissues; Transgenic Mice; Vascular remodeling; Vascular resistance; Vasodilator Agents; WNT Signaling Pathway; beta catenin; bioinformatics tool; candidate identification; cell type; cellular targeting; drug isolation; drug testing; effective therapy; experimental study; genetic testing; hemodynamics; improved; in vivo; inhibitor; mortality; mouse genetics; neointima formation; notch protein; novel; prevent; pulmonary arterial hypertension; right ventricular failure; single cell analysis; single-cell RNA sequencing

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.

项目总结/摘要 肺动脉高压（PH）是一种致命的肺动脉疾病， 治疗和没有治愈。在PH中，闭塞性“新生内膜病变”在小肺动脉内生长， 动脉和狭窄的血管腔，增加肺血管阻力，最终 导致右心衰竭和死亡可用的PH疗法是血管扩张剂， 靶向新生内膜生长，既不能阻止疾病进展，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。在初步研究中，我们发现增生的新生内膜 细胞与动脉内皮细胞相邻，并具有不同的基因表达， 它们来自远离内皮的细胞。我们假设一种分子定义的 位于内皮附近的新生内膜细胞的亚群是增殖部分， 扩张新生内膜损伤，来自内皮的信号调节损伤生长。 具体目的：（1）利用增殖追踪、遗传谱系追踪和消除， 从分子上表征新生内膜细胞的亚群，其增殖负责 病变生长(2)通过对新生内膜中单细胞转录的生物信息学分析， 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中的增殖以及小鼠和人类之间共有的核心疾病机制。（三） 检测新生内膜增殖的关键候选驱动因素在以下疾病中病变生长中的作用的能力： 多个PH模型。在这里，通过利用尖端技术，遗传学和单细胞 通过跨多个模型系统的方法，这些实验将提供一个粒度 了解驱动新生内膜病变扩张的细胞和信号， 根据目前对PH患者血管重塑病理学的了解， 希望最终能带来新内膜阻断治疗方案。