Coordinated regeneration of lung epithelial and endothelial compartments

肺上皮和内皮室的协调再生

基本信息

批准号：
10687177
负责人：
Andrew Vaughan
金额：
$ 55.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687177
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Address Alveolar Animals Automobile Driving Binding Biological Assay Blood Vessels Blood capillaries COVID-19 Capillary Endothelial Cell Cell Death Cell Proliferation Cells ChIP-seq Data Elderly Endoglin Endothelial Cells Endothelium Epithelial Cell Proliferation Epithelial Cells Epithelium Exposure to Fibrosis Gases Genes Glycoproteins Hypoxemia Immunocompromised Host In Vitro Individual Infection Influenza Influenza A Virus, H1N1 Subtype Injury Lung MADH2 gene Mediating Modeling Molecular Mus Natural regeneration Organoids Pathogenicity Pathologic Pathway interactions Patients Persons Physiological Proliferating Proteins Public Health Pulmonary Edema Recovery Regenerative response Reporting Role Signal Pathway Signal Transduction TGFBR2 gene Testing Therapeutic Toxin Transforming Growth Factor beta Transforming Growth Factor beta Receptors Up-Regulation Vascular Endothelium Vascular regeneration Viral Pneumonia Work alveolar epithelium angiogenesis antagonist autocrine capillary bed design endothelial regeneration endothelial repair epithelial repair epithelium regeneration improved in vivo inducible Cre influenza virus strain lung injury lung repair mortality novel overexpression pandemic disease pathogen prevent progenitor protective pathway pulmonary function receptor regeneration function regeneration potential repair function repaired respiratory virus seasonal influenza single-cell RNA sequencing targeted treatment tissue repair transcriptome sequencing transcriptomics

项目摘要

Influenza alone kills as many as 500,000 people annually, and at least 4.5 million have died from SARS-CoV-2 during this ongoing pandemic, with mortality from both respiratory viruses largely due to viral pneumonia progressing to acute respiratory distress syndrome (ARDS). Significant focus has been placed on regeneration of the epithelium after influenza, but relatively little is known as to how the endothelium is repaired, a critical question since vascular endothelial integrity is necessary to prevent ARDS-associated pulmonary edema, hypoxemia, and mortality. We recently demonstrated that at least 20% of the lung's vascular endothelium is regenerated by 1 month after infection, indicating a robust capacity for endothelial repair. We therefore investigated signaling pathways which might modulate this regenerative functionality. Somewhat unexpectedly given its role in promoting fibrosis, we observed that endothelial- specific blockade of TGF-β signaling prevents effective repair of the lung endothelium and results in inefficient physiologic recovery. Moreover, in order to achieve coordinated, functional tissue repair, we reasoned that lung endothelial cells might influence repair of the adjacent epithelium by release of angiocrine factors. In keeping with this notion, we identified a matricellular protein, SPARCL1, which is secreted by injury-activated endothelial cells and serves to enhance alveolar epithelial regeneration, at least in part by modulating TGF-β. Based on our cumulative findings, we hypothesize that injury-activated endothelial cells engage a TGF-β / SPARCL1 axis to coordinately regulate lung endothelial and epithelial repair. The major objectives to address this hypothesis are 1) mechanistically define how TGF-β promotes lung vascular repair and 2) determine whether and how SPARCL1 acts as an angiocrine factor to promote alveolar epithelial regeneration. Successful completion of these studies will inform approaches designed to enhance endothelial cell regenerative potential and promote effective lung repair / prevent mortality in ARDS and viral pneumonia.

仅流感每年就夺走多达 50 万人的生命，其中至少有 450 万人死亡在这场持续的大流行期间，来自 SARS-CoV-2 的病毒，两种呼吸道病毒均导致死亡很大程度上是由于病毒性肺炎进展为急性呼吸窘迫综合征（ARDS）。人们重点关注流感后上皮的再生，但相对而言人们对内皮如何修复知之甚少，这是自血管生成以来的一个关键问题内皮完整性对于预防 ARDS 相关的肺水肿、低氧血症、我们最近证明，至少 20% 的肺血管内皮细胞是血管内皮细胞。感染后1个月即可再生，表明内皮修复能力强。因此研究了可能调节这种再生功能的信号通路。考虑到其在促进纤维化方面的作用，我们观察到内皮- 特异性阻断 TGF-β 信号传导可阻止肺内皮的有效修复导致生理恢复效率低下，无法实现协调的功能。组织修复，我们推测肺内皮细胞可能影响邻近邻近组织的修复与这一概念一致，我们确定了一种通过释放血管分泌因子来抑制上皮细胞的生长。基质细胞蛋白 SPARCL1，由损伤激活的内皮细胞分泌至少部分通过调节 TGF-β 来增强肺泡上皮再生。根据我们的累积发现，我们发现损伤激活的内皮细胞参与 TGF-β/SPARCL1 轴协调调节肺内皮和上皮修复。解决这一假设的主要目标是 1) 机械地定义 TGF-β 如何促进肺血管修复，2) 确定 SPARCL1 是否以及如何充当血管分泌因子促进肺泡上皮再生成功完成这些。研究将为旨在增强内皮细胞再生潜力的方法提供信息促进有效的肺部修复/预防急性呼吸窘迫综合征和病毒性肺炎的死亡。