Cellular and molecular mechanisms of alveolar repair

肺泡修复的细胞和分子机制

基本信息

批准号：
10750085
负责人：
Tushar Jasubhai DESAI
金额：
$ 67.38万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750085
关键词：
3-Dimensional AGTR2 gene Ablation Activities of Daily Living Acute Acute Lung Injury Acute Respiratory Distress Syndrome Adrenal Cortex Hormones Adult Aging Alleles Alveolar Alveolar Cell Anti-Inflammatory Agents Antibiotics Bacterial Pneumonia Biology Blood Vessels Blood capillaries Capillary Endothelial Cell Cause of Death Cell Differentiation process Cell Proliferation Cells Cessation of life Chronic Cytokinesis Data EGFR inhibition Electrons Endothelial Cells Endothelium Engineering Epidermal Growth Factor Receptor Epithelium Failure Fibroblasts Functional disorder Gases Goals Hand Hyperplasia Hypoxemic Respiratory Failure Impairment Individual Influenza A Virus, H1N1 Subtype Injury Kinetics Knowledge Learning Liquid substance Lung Maintenance Maps Measures Mechanical ventilation Microscopic Mitosis Modeling Molecular Mononuclear Mus Natural regeneration Nuclear Outcome Oxygen Pathogenesis Pathologic Permeability Pharmaceutical Preparations Phenotype Physiologic pulse Physiological Population Process Proliferating Property Pulmonary Edema Regenerative response Research Resolution Respiratory Failure Respiratory distress Series Signal Transduction Site Structure Testing Vascular Permeabilities WNT Signaling Pathway Work alveolar epithelium beta catenin cell growth regulation cell injury cell killing cell regeneration cell type comparative effective therapy epithelial repair epithelium regeneration influenza pneumonia injury and repair molecular dynamics molecular targeted therapies mouse genetics novel prevent progenitor programs reconstitution regenerative repaired response restoration stem cell proliferation stem cells supplemental oxygen surfactant function temporal measurement tool transcriptome sequencing transdifferentiation

项目摘要

PROJECT SUMMARY Death or chronic lung dysfunction from acute respiratory distress syndrome (ARDS) is a dreaded consequence of acute injury to the alveolar gas exchange region of lung. Other than antibiotics for bacterial pneumonia and in some cases anti-inflammatory medications like corticosteroids, there are no specific therapies beyond supplementary oxygen and ventilatory support. Thus, there is an urgent need to better understand how acute alveolar injury is repaired and in cases when this is insufficient, what are the reasons for the failure to recover gas exchange function. Once the precise cellular and molecular regenerative and maladaptive alveolar responses are identified, we can move on to rationally engineer novel and specific treatments to promote repair. We have recently mapped at high resolution the alveolar regenerative response to alveolar epithelial type I (AT1) cell ablation, which revealed several unexpected mechanisms. In addition to conventional AT2 stem cell proliferation, we identified two other regenerative mechanisms. The first was immediate transdifferentiation of AT2 cells without prior proliferation, followed by mitosis of resident binucleated AT2 progenitors found in healthy lungs. We also identified pathological responses from repeated AT1 cell ablation consisting of excessive AT2 stem cell proliferation with loss of surfactant function and impaired AT1 cell differentiation. Here, we plan to flesh out the molecular and cellular regulation of these regenerative programs and to determine their physiological impact on maintaining proper gas exchange by preventing capillary leak and pulmonary edema. In summary, we will apply precise cell type ablation and injury with state-of-the-art experimental approaches to clarify at high temporal resolution the cellular and molecular basis of alveolar epithelial repair.

项目摘要急性呼吸窘迫综合征（ARDS）的死亡或慢性肺功能障碍是可怕的后果肺肺泡交换区域的急性损伤。除了抗生素用于细菌性肺炎和在某些情况下，抗炎药（例如皮质类固醇），除了补充氧和通气支持。因此，迫切需要更好地了解修复肺泡损伤，在不足的情况下，未能恢复的原因是什么气体交换功能。一旦精确的细胞和分子再生和不良适应性肺泡确定了反应，我们可以继续进行理性工程师的小说和特定处理以促进维修。我们最近以高分辨率绘制了对肺泡上皮的肺泡再生反应 I型（AT1）细胞消融，揭示了几种意外的机制。除了常规AT2 干细胞增殖，我们确定了另外两种再生机制。第一个是立即的没有事先增殖的AT2细胞的转变，然后进行有丝分裂的居民双核AT2 在健康肺中发现的祖细胞。我们还确定了重复AT1细胞消融中的病理反应由过度AT2干细胞增殖和表面活性剂功能损失组成并受损AT1细胞分化。在这里，我们计划充实这些再生程序的分子和细胞调节并通过防止毛细管泄漏来确定他们对维持适当气体交换的生理影响和肺水肿。总而言之，我们将使用最先进的精确细胞类型消融和伤害实验方法在高时间分辨率上阐明肺泡的细胞和分子基础上皮修复。