Role of Lung MSC in Emphysema

肺间充质干细胞在肺气肿中的作用

• 批准号: 9898030
• 负责人: SUSAN M MAJKA
• 金额: $ 63.29万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-21 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898030
• 关键词: Address; Adult; Affect; Attenuated; Binding; Biological Assay; Blood Vessels; 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; 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; in vivo; in vivo Model; indexing; knock-down; migration; mortality; mouse model; novel; outcome forecast; overexpression; paracrine; progenitor; receptor; response; response to injury

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。 States.慢性阻塞性肺疾病常因血管病变而加重，严重影响预后并限制生存。 血管病变的特征在于微血管的重塑和损失。最近的证据还强调， 在COPD的早期发病机制和异质性中微血管改变的作用， 尽管没有定义基本机制。本提案的目标是解决这些知识 通过定义相互间充质祖细胞-内皮细胞 相互作用调节肺微血管结构和COPD的发展。在上一次融资中， 周期，我们报道了一种新的间充质祖细胞（MPC）群体的存在， 周细胞的祖细胞，因此需要维持微血管稳态。我们进一步 报道Wnt/β-catenin信号传导是这种MPC功能的重要调节因子。但如何 MPC中Wnt信号传导增加，其调节剂Dkk 1的产生和血管病变的发展 影响气体交换的表面，COPD的病理生理学尚不清楚。因此了解 MPC中的Wnt信号传导对于促进微血管和组织功能将是重要的。小说的前提 这一观点认为，MPCs内增强的Wnt/β-catenin信号传导间接导致肺气肿和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Wnt/β-连环蛋白的增加通过1）Dkk 1的产生增加和B）a Dkk 1对微血管内皮细胞功能的旁分泌作用我们将测试Wnt/β- MPC中的连环蛋白通过增加Dkk 1的MPC表达和随后的Dkk 1的旁分泌改变导致COPD。 微血管内皮细胞命运特化。为了检测MPC中β-catenin和Dkk 1的表达是否与 对于COPD中MPC-MVEC串扰和组织重塑的维持至关重要，我们将有条件地敲 降低或过度表达MPC中的Dkk 1和β-catenin，并使小鼠暴露于烟雾或血管损伤。我们会委聘 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标 和屏障功能的测量。我们还将测试MPC-MVEC相互作用的维持， 操纵Dkk 1信号传导将减弱微血管功能和组织结构的丧失， 损伤我们将在体外操纵人和小鼠肺MPCs中的Dkk 1/Wnt信号传导，并抑制Dkk 1/Wnt信号传导。 信号转导，以评估MVEC功能受影响的机制。这些 研究将确定在MVEC中调节MPC或抑制/敲除Dkk 1信号传导是否是可行的。 以促进微血管功能和减轻COPD为目标。我们提出的研究将推动这一领域的发展， 通过定义MPC调节微血管内皮功能的Wnt依赖性机制， 通过重新利用FDA批准的DKK 1调节剂，逆转COPD中的血管病变。