Coordinated regeneration of lung epithelial and endothelial compartments

肺上皮和内皮室的协调再生

• 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
• 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

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.

仅流感一项每年就造成多达50万人死亡，至少有450万人死亡 在这场持续的大流行期间， 主要是由于病毒性肺炎发展为急性呼吸窘迫综合征（ARDS）。 流感后上皮细胞的再生一直是人们关注的焦点，但相对而言， 关于内皮细胞是如何修复的知之甚少，这是一个关键问题，因为血管内皮细胞是如何修复的。 内皮完整性对于防止ARDS相关的肺水肿，低氧血症， and mortality.我们最近证明，至少有20%的肺血管内皮细胞 感染后1个月再生，表明内皮修复的强大能力。我们 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中的作用，我们观察到内皮细胞- TGF-β信号传导的特异性阻断阻止肺内皮的有效修复， 导致生理恢复不充分。此外，为了实现协调，功能 组织修复，我们推断肺内皮细胞可能会影响邻近组织的修复。 上皮细胞通过释放血管分泌因子。根据这一概念，我们确定了一个 基质细胞蛋白SPARCL 1，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。基于 根据我们的累积发现，我们假设损伤激活的内皮细胞参与了 TGF-β /SPARCL 1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）从机制上定义TGF-β如何 促进肺血管修复和2）确定SPARCL 1是否以及如何作为一个 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， 促进有效的肺修复/预防ARDS和病毒性肺炎的死亡率。