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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.

项目总结/摘要该提案的总体目标是提供关于过度积累的关键见解，平滑肌细胞（SMC）是多种血管病变的特征。Greif实验室和其他研究小组已经表明，动脉粥样硬化或缺氧诱导的病理性重塑涉及鲁棒的，罕见的SMC祖细胞的克隆扩增。在此，我们建议研究巨噬细胞介导的血管疾病中SMC祖细胞的调节。我们最近发现了一个平滑肌细胞库，我们称之为“启动”细胞（如启动肌肉化）的祖细胞，位于每个细胞的肺中的肌-肌间无肌小动脉边界，并具有独特的分子特征， SMC标志物和未分化间充质标志物血小板源性生长因子受体随着缺氧暴露，这些祖细胞之一克隆扩增，产生大量的PDGFR-β。大多数平滑肌细胞覆盖着正常无肌化的远端小动脉。但是它们在随后的血管重塑中的作用还不清楚。我们的最初的研究表明，缺氧肺中的巨噬细胞具有增强的缺氧-耐受水平，诱导因子（HIF）-α和配体血小板源性生长因子（PDGF）-β B。此外，我们证明了在小鼠中Pdgfb缺失具有两个独立的敲除（LysM-PdgCre或Csf 1 r-PdgCreER），诱导巨噬细胞/单核细胞重组，减弱缺氧诱导的远端小动脉此外，巨噬细胞耗竭抑制病理性血管重塑。假设肺巨噬细胞HIF-α是低氧诱导PDGF-B B所需细胞自主性表达，巨噬细胞来源的PDGF-β B对启动的SMC增殖至关重要，为了验证这一假设，我们将利用转基因技术，小鼠、从小鼠肺以及人肺分离的致敏细胞和巨噬细胞亚群单核细胞和肺动脉平滑肌细胞。我们已经仔细组装了一组顶尖的具有不同专业知识的合作者，从血管和肺部疾病中的巨噬细胞到纳米粒子的生物工程，这将有助于使该提案取得成果。该提案本研究的主要目的是：1）阐明巨噬细胞来源的PDGF-β B的细胞机制低氧诱导远端肺小动脉肌化; 2）评估特异性缺氧/PDGFB-CRP诱导的肺血管重塑中的巨噬细胞群; 确定巨噬细胞缺氧诱导因子-α在缺氧诱导的血小板源性生长因子-α B表达和血小板源性生长因子-α B-α中的作用介导的远端肌肉化。总之，所提出的研究将产生对巨噬细胞-巨噬细胞-SMC祖细胞相互作用在血管疾病中的作用，从而提示新的治疗策略