Molecular mechanisms of alveolar development and regeneration

肺泡发育和再生的分子机制

• 批准号: 10201731
• 负责人: PAO-TIEN CHUANG
• 金额: $ 51.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201731
• 关键词: Ablation; Actomyosin; Adopted; Adult; Affect; Alveolar; Alveolar Cell; Alveolar Cell Type I; Biological Assay; Bleomycin; Bronchopulmonary Dysplasia; Candidate Disease Gene; Cell Communication; Cell Shape; Cell physiology; Cells; Chronic Obstructive Airway Disease; Cytoskeleton; Defect; Development; Diagnosis; Distal; Electron Microscopy; Epithelial; Epithelial Cells; Failure; Foundations; Future; Genetic; Goals; Human; Knowledge; Ligands; Lung; Lung diseases; Mediating; Membrane; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Analysis; Mus; Myofibroblast; Natural regeneration; Nature; Neonatal; Organoids; Pathogenesis; Pathway interactions; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Process; Resolution; Role; Signal Pathway; Signal Transduction; Stromal Cells; System; Techniques; Technology; Testing; Type I Epithelial Receptor Cell; alveolar type II cell; cell type; design; genetic analysis; human disease; insight; light microscopy; lung development; lung imaging; lung injury; planar cell polarity; receptor; reconstitution; regenerative; response; transcriptome sequencing

Project Summary/Abstract This application aims to elucidate the molecular mechanisms of alveolar formation during development and in response to lung injury. We anticipate that our study will provide new insight into the pathogenesis of human lung diseases caused by the failure of alveolar development or regeneration, notably bronchopulmonary dysplasia (BPD) and chronic obstructive lung disease (COPD), respectively. In preliminary studies, we have discovered a critical role of planar cell polarity (PCP) in controlling alveolar formation. In this proposal, we aim to test how PCP signaling mediates cell-cell interactions between alveolar cells and mesenchymal myofibroblasts, leading to PDGF signaling, cell shape changes and alveolar formation. Our specific aims are: (1) To test the hypothesis that Vangl2-mediated planar cell polarity is required for PDGF signaling and cell shape changes during alveolar formation in development; (2) To test the hypothesis that a Wnt5a-Vangl2 axis controls alveolar formation; and (3) To molecularly characterize realveolarization following lung injury in adults. Taken together, these studies will increase our mechanistic understanding of alveolar formation during development and following lung injury and facilitate future diagnosis and treatment of lung diseases caused by loss of alveoli.

项目摘要/摘要 这一应用旨在阐明发育过程中肺泡形成的分子机制。 对肺损伤的反应。我们期待我们的研究将为人类的发病机制提供新的见解。 肺泡发育或再生失败引起的肺部疾病，尤其是支气管肺病 不典型增生(BPD)和慢性阻塞性肺疾病(COPD)。在初步研究中，我们有 发现了平面细胞极性(PCP)在控制肺泡形成中的关键作用。在这项提案中，我们的目标是 检测PCP信号如何调节肺泡细胞和间质之间的细胞间相互作用 肌成纤维细胞，导致PDGF信号转导，细胞形态改变和肺泡形成。我们的具体目标是： (1)验证Vangl2介导的平面细胞极性是PDGF信号和细胞所必需的假设 (2)检验Wnt5a-Vangl2轴的假设 控制肺泡的形成；以及(3)对成人肺损伤后的肺泡化进行分子表征。 综上所述，这些研究将增加我们对肺泡形成机制的理解 发展和继发的肺损伤，并促进未来的诊断和治疗引起的肺部疾病 由于肺泡的丧失。

项目成果

A functional circuit formed by the autonomic nerves and myofibroblasts controls mammalian alveolar formation for gas exchange.

• DOI: 10.1016/j.devcel.2022.05.021
• 发表时间: 2022-07-11
• 期刊: DEVELOPMENTAL CELL
• 影响因子: 11.8
• 作者: Zhang, Kuan;Yao, Erica;Wang, Shao-An;Chuang, Ethan;Wong, Julia;Minichiello, Liliana;Schroeder, Andrew;Eckalbar, Walter;Wolters, Paul J.;Chuang, Pao-Tien
• 通讯作者: Chuang, Pao-Tien

Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria.

• DOI: 10.7554/elife.68598
• 发表时间: 2022-04-06
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Zhang, Kuan;Yao, Erica;Chen, Biao;Chuang, Ethan;Wong, Julia;Seed, Robert, I;Nishimura, Stephen L.;Wolters, Paul J.;Chuang, Pao-Tien;Koenigshoff, Melanie
• 通讯作者: Koenigshoff, Melanie

mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.

• DOI: 10.1038/s41467-022-34763-y
• 发表时间: 2022-11-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Zhang, Kuan;Yao, Erica;Chuang, Ethan;Chen, Biao;Chuang, Evelyn Y.;Chuang, Pao-Tien
• 通讯作者: Chuang, Pao-Tien

Wnt5a-Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions.

• DOI: 10.1371/journal.pbio.3001759
• 发表时间: 2022-08
• 期刊: PLOS BIOLOGY
• 影响因子: 9.8
• 作者: Zhang, Kuan;Yao, Erica;Chuang, Ethan;Chen, Biao;Chuang, Evelyn Y.;Volk, Regan F.;Hofmann, Katherine L.;Zaro, Balyn;Chuang, Pao-Tien
• 通讯作者: Chuang, Pao-Tien