Role of Lung MSC in Emphysema

肺间充质干细胞在肺气肿中的作用

基本信息

批准号：
10153854
负责人：
SUSAN M MAJKA
金额：
$ 61.68万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-21 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153854
关键词：
Address Adult Affect Attenuated Binding Biological Assay Cell Communication Cell Differentiation process Cell physiology Cells Chronic Obstructive Airway Disease Data Development Distal Endothelial Cells Endothelium FDA approved Functional disorder Funding Gases Goals Heterogeneity Histologic Homeostasis Human In Vitro Injury Knock-out Knowledge Ligands Lung Lung diseases Lupus erythematosus cell Maintenance Malignant Neoplasms Measures Mediator of activation protein Mesenchymal Mesenchymal Stem Cells Modeling Molecular Mus Optical Coherence Tomography Pathogenesis Pathway interactions Patients Pericytes Phenotype Population Production Prognosis Proteins Publishing Pulmonary Emphysema Receptor Signaling Regulation Reporting Role SU 5416 Scanning Signal Transduction Smoke Smooth Muscle Myocytes Structure Structure of parenchyma of lung Surface Testing Time Tissues United States Vascular Diseases Vascular Endothelium Vegf inhibition WNT Signaling Pathway angiogenesis base beta catenin cell fate specification clinically relevant endothelial stem cell in vivo in vivo Model indexing knock-down migration mortality mouse model novel overexpression paracrine progenitor receptor response response to injury stem cell function vascular injury

项目摘要

Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States. COPD often is exacerbated by vasculopathy, which substantially worsens prognosis and limits survival. Vasculopathy is characterized by remodeling and loss of microvessels. Recent evidence has also highlighted a role for the alterations to the microvasculature during the early pathogenesis and heterogeneity of COPD, although the underlying mechanisms are not defined. The goal of this proposal is to address this knowledge gap by defining the molecular mechanisms whereby reciprocal mesenchymal progenitor-endothelial cell interactions regulate pulmonary microvascular structure and the development of COPD. In the last funding cycle, we reported the existence of a novel population of mesenchymal progenitor cells (MPC) which serve as progenitors for pericytes and therefore are required to maintain microvascular homeostasis. We further reported that Wnt/β-catenin signaling was an important regulator of this MPC function. However, how increased Wnt signaling in MPC, production of its modulator Dkk1 and the development of vasculopathy impacts surfaces for gas exchange and the pathophysiology of COPD is unknown. Therefore, understanding Wnt signaling in MPC, will be important to facilitate microvascular and tissue function. The novel premise of this proposal is that enhanced Wnt/β-catenin signaling within MPCs indirectly leads to emphysema and COPD by altering normal MPC-microvascular endothelial cell (MVEC) interactions. We hypothesize that activation of Wnt/β-catenin in MPC exacerbates the onset of COPD via 1) increased production of Dkk1 and b) a paracrine effect of Dkk1 on microvascular endothelial cell function. We will test that activation of Wnt/β- catenin in MPCs leads to COPD via increased MPC expression of Dkk1 and subsequent paracrine alteration of microvascular endothelial cell-fate specification. To test whether MPC expression of β-catenin and Dkk1 are critical for maintenance of MPC-MVEC cross talk and tissue remodeling in COPD, we will conditionally knock down or overexpress Dkk1 and β-catenin in MPC and expose mice to smoke or vascular injury. We will employ novel models of lineage analyses, optical coherence tomography (OCT), histological indices of angiogenesis and measures of barrier function. We will also test that maintenance of MPC-MVEC interaction via manipulation of Dkk1 signaling will attenuate loss of microvascular function and tissue structure following injury. We will manipulate Dkk1/Wnt signaling in human and mouse lung MPCs in vitro and inhibit Dkk1 signaling in murine models in vivo, to evaluate the mechanism by which MVEC function is affected. These studies will determine whether modulation of MPC, or inhibition / knockout Dkk1 signaling in MVEC is a viable target to promote microvascular function and attenuate COPD. Our proposed studies will advance the field of by defining Wnt dependent mechanisms by which MPC regulate microvascular endothelial function and identify targets to reverse vasculopathy in COPD, by repurposing of FDA approved DKK1 modulators.

慢性阻塞性肺疾病（COPD）是统一死亡率的第三主要原因国家。 COPD通常会因血管病而加剧，这显着恶化了预后，并限制了存活率。血管病的特征是重塑和微血管丧失。最近的证据也强调了在早期发病机理和COPD的异质性期间对微脉管系统改变的作用，尽管未定义的基本机制。该提议的目的是解决这一知识通过定义分子机制的间隙，从而使间质祖细胞 - 骨膜内皮细胞相互作用调节肺微血管结构和COPD的发展。在最后的资金中循环，我们报道了一种新型间充质祖细胞（MPC）的存在，这些人数是周围的祖细胞，因此需要维持微血管稳态。我们进一步报道Wnt/β-catenin信号传导是该MPC功能的重要调节剂。但是，如何 MPC中的Wnt信号增加，其调节剂DKK1的产生和脉管病的发展气体交换的影响表面和COPD的病理生理尚不清楚。因此，理解 MPC中的Wnt信号传导对于促进微血管和组织功能很重要。小说的前提该建议是，MPC内的Wnt/β-catenin信号增强了，间接导致肺气肿和COPD 通过改变正常的MPC微血管内皮细胞（MVEC）相互作用。我们假设激活 MPC中的Wnt/β-catenin of COPD的发作通过1）增加了DKK1的产生和b）a DKK1对微血管内皮细胞功能的旁分泌作用。我们将测试Wnt/β-的激活 MPC中的Catenin通过增加DKK1的MPC表达和随后的旁分泌改变而导致COPD 微血管内皮细胞粘液规范。测试MPC表达β-catenin和dkk1是否是对于维持MPC-MVEC横式谈话和COPD的组织重塑至关重要，我们将有条件敲门在MPC中向下或过表达DKK1和β-catenin，并暴露小鼠烟雾或血管损伤。我们将雇用谱系分析的新型模型，光学相干断层扫描（OCT），血管生成的组织学指标和屏障功能的度量。我们还将测试MPC-MVEC互动的维护 DKK1信号的操纵将减弱微血管功能和组织结构的丧失受伤。我们将在体外操纵人和小鼠肺MPC中的DKK1/WNT信号传导，并抑制DKK1 在体内鼠模型中的信号传导，以评估MVEC功能受影响的机制。这些研究将确定MVEC中MPC的调制或抑制 /敲除DKK1信号是可行的促进微血管功能并减弱COPD的目标。我们提出的研究将推动通过定义MPC调节微血管内皮功能的依赖性机制并识别通过重新利用FDA批准的DKK1调节剂来逆转COPD中的血管病。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.

DOI：
10.1161/jaha.112.005157
发表时间：
2013-01-16
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Meloche J;Courchesne A;Barrier M;Carter S;Bisserier M;Paulin R;Lauzon-Joset JF;Breuils-Bonnet S;Tremblay É;Biardel S;Racine C;Courture C;Bonnet P;Majka SM;Deshaies Y;Picard F;Provencher S;Bonnet S
通讯作者：
Bonnet S