Vascular disease pathogenesis: the interface of smooth muscle and immune cells

血管疾病发病机制：平滑肌与免疫细胞的界面

基本信息

批准号：
9769127
负责人：
Daniel Greif
金额：
$ 57.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769127
关键词：
Adoptive Cell Transfers Adult Alveolar Apoptosis Artificial nanoparticles Atherosclerosis Attenuated Biology Biomedical Engineering Blood Vessels Cell Proliferation Cells Cellular biology Clinical Investigator Clonal Expansion Clonality Clone Cells Conditioned Culture Media Development Distal Endothelial Cells Endothelium Fruit Genetic Recombination Glycocalyx Goals Human Hypoxia Hypoxia Inducible Factor Immune Inflammatory Knock-in Mouse Ligands Lung Lung diseases Mediating Mesenchyme Molecular Profiling Mus Muscle PDGFB gene Pathogenesis Pathologic Pathology Patients Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor beta Receptor Play Population Process Proto-Oncogene Proteins c-sis Pulmonary Hypertension Pulmonary artery structure Regulation Research Personnel Right Ventricular Hypertrophy Role Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Stem cells Subgroup Sum Testing Therapeutic Transgenic Mice Tube Undifferentiated VHL gene Vascular Diseases Vascular remodeling arteriole cell dedifferentiation hypoxia inducible factor 1 insight interstitial knock-down macrophage migration monocyte nanoparticle nanoparticle delivery notch protein novel therapeutics progenitor recruit vascular factor

项目摘要

PROJECT SUMMARY / ABSTRACT The overall goal of this proposal is to provide key insights into the excess accumulation of smooth muscle cells (SMCs) that characterizes multiple vascular pathologies. The Greif lab and other groups have shown that pathological remodeling induced in atherosclerosis or hypoxia involves robust clonal expansion of rare SMC progenitors. Herein, we propose to study the macrophage-mediated regulation of SMC progenitors in vascular disease. We recently identified a pool of smooth muscle progenitors that we have termed “primed” cells (as in primed to muscularize), located at each muscular-unmuscular arteriole border in the lung and with a unique molecular signature expressing SMC markers and the undifferentiated mesenchyme marker platelet-derived growth factor receptor (PDGFR)-β. With hypoxia exposure, one of these progenitors clonally expands giving rise to the vast majority of SMCs that coat the normally unmuscularized distal arteriole. Macrophages accumulate in the lung with hypoxia but their role in the ensuing vascular remodeling is not well understand. Our initial studies demonstrate that macrophages in the hypoxic lung have enhanced levels of hypoxia- inducible factor (HIF)-α and the ligand platelet-derived growth factor (PDGF)-B. Furthermore, we demonstrate that deletion of Pdgfb with two independent knock-in mice (LysM-Cre or Csf1r-CreER), which induce recombination in macrophages/monocytes, attenuates hypoxia-induced distal arteriole muscularization. Additionally, macrophage depletion inhibits pathological vascular remodeling. We hypothesize that lung macrophage HIF-α is required cell autonomously for hypoxia-induced PDGF-B expression, and macrophage-derived PDGF-B is critical for primed SMC proliferation and dedifferentiation in pulmonary vascular remodeling. To test this hypothesis, we will utilize transgenic mice, primed cells and macrophage subpopulations isolated from the mouse lung as well as human monocytes and pulmonary artery SMCs. We have carefully assembled a group of top-notch collaborators with diverse expertise, ranging from macrophages in vascular and lung diseases to bioengineering of nanoparticles, which will facilitate bringing the proposal to fruition. This proposal specifically aims to: 1) elucidate cellular mechanisms underlying macrophage-derived PDGF-B induction of distal pulmonary arteriole muscularization in hypoxia;; 2) assess role of specific macrophage populations in hypoxia/PDGFB-induced pulmonary vascular remodeling;; and 3) determine the role of macrophage HIF-α in hypoxia-induced PDGF-B expression and in PDGF-B- mediated distal muscularization. In sum, the proposed studies will yield fundamental insights into the role of macrophage-SMC progenitor interactions in vascular disease and thereby suggest novel therapeutic strategies.

项目摘要/摘要该提案的总体目标是提供有关超额积累的关键见解表征多种血管病理的平滑肌细胞（SMC）。 Greif实验室和其他组表明，在动脉粥样硬化或缺氧中衍生的病理重塑涉及强大稀有SMC祖细胞的克隆扩张。在此，我们建议研究巨噬细胞介导的调节血管疾病中SMC祖细胞。我们最近确定了平滑肌池我们称之为“底漆”细胞的祖细胞（如肌肉发达的肌肉化）肺部的肌肉 - 无肌肉边界，并具有独特的分子特征表达 SMC标记和未分化的间充质标志物血小板衍生的生长因子接收器（PDGFR）-β。随着缺氧的暴露，克隆的祖细胞中的一位扩大，从而产生了新的大多数SMC覆盖通常无肌的远端动脉。巨噬细胞积累患有缺氧的肺，但在随后的血管重塑中的作用尚不清楚。我们的最初的研究表明，低氧肺中的巨噬细胞具有增强的缺氧水平。诱导因子（HIF）-α和配体血小板衍生的生长因子（PDGF）-b。此外，我们证明用两只独立的敲门小鼠（Lysm-Cre或CSF1R-Creer）删除PDGFB，诱导巨噬细胞/单核细胞中的重组，可减弱缺氧引起的远端小动脉肌肉化。另外，巨噬细胞的耗竭抑制病理血管重塑。我们假设肺巨噬细胞HIF-α是缺氧诱导的PDGF-B自主的细胞表达和巨噬细胞衍生的PDGF-B对于引发SMC增殖至关重要肺血管重塑的去分化。为了检验这一假设，我们将利用转基因从小鼠肺和人类分离的小鼠，底漆细胞和巨噬细胞亚群单核细胞和肺动脉SMC。我们已经仔细组装了一组一流的具有潜水专业知识的合作者，从血管和肺部疾病的巨噬细胞到纳米颗粒的生物工程，这将有助于提出该提议。这个建议特别旨在：1）阐明巨噬细胞衍生的PDGF-B的细胞机制在缺氧中诱导圆盘肺动脉肌肉化； 2）评估特定的角色缺氧/PDGFB诱导的肺血管重塑中的巨噬细胞种群； 3）确定巨噬细胞HIF-α在缺氧诱导的PDGF-B表达以及PDGF-B-中的作用介导的远端肌肉。总而言之，拟议的研究将产生对巨噬细胞-SMC祖细胞相互作用在血管疾病中的作用，因此表明了新颖的治疗策略。