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）是美国第三大死亡原因慢性阻塞性肺病常常因血管病变而加剧，这大大恶化了预后并限制了生存。血管病变的特点是微血管重塑和丧失。慢性阻塞性肺病早期发病机制和异质性中微脉管系统改变的作用，尽管底层机制尚未定义，但该提案的目标是解决这一问题。通过定义间充质祖细胞-内皮细胞相互作用的分子机制来研究间隙相互作用调节肺微血管结构和 COPD 的发展。周期中，我们报告了一种新的间充质祖细胞（MPC）群体的存在，其充当周细胞的祖细胞因此需要维持微血管稳态。据报道，Wnt/β-连环蛋白信号传导是这种 MPC 功能的重要调节因子。 MPC 中 Wnt 信号传导的增加、其调节剂 Dkk1 的产生以及血管病变的发展其对气体交换表面的影响和 COPD 的病理生理学尚不清楚。 MPC 中的 Wnt 信号传导对于促进微血管和组织功能至关重要。该提议认为，MPC 内增强的 Wnt/β-catenin 信号传导会间接导致肺气肿和 COPD 通过改变正常的 MPC-微血管内皮细胞 (MVEC) 相互作用。 MPC 中 Wnt/β-连环蛋白通过 1) 增加 Dkk1 的产生和 b) a 使 COPD 的发作恶化 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 中的连环蛋白通过 Dkk1 的 MPC 表达增加以及随后的旁分泌改变导致 COPD 测试微血管内皮细胞命运规范是否是 β-catenin 和 Dkk1 的 MPC 表达。对于 COPD 中 MPC-MVEC 串扰的维持和组织重塑至关重要，我们将有条件地敲击我们将在 MPC 中下调或过度表达 Dkk1 和 β-catenin，并将小鼠暴露于烟雾或血管损伤中。谱系分析的新模型、光学相干断层扫描 (OCT)、血管生成的组织学指数我们还将测试 MPC-MVEC 相互作用的维持。操纵 Dkk1 信号传导将减轻微血管功能和组织结构的丧失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。体内小鼠模型中的信号传导，以评估影响 MVEC 功能的机制。研究将确定在 MVEC 中调节 MPC 或抑制/敲除 Dkk1 信号传导是否可行我们提出的研究将促进微血管功能和减轻慢性阻塞性肺病（COPD）领域的发展。通过定义 MPC 调节微血管内皮功能的 Wnt 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 的血管病变。

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