AP-1 as a transcriptional regulator of AT2 cell reversible activation during lung injury response

AP-1 作为肺损伤反应期间 AT2 细胞可逆激活的转录调节因子

• 批准号: 10843725
• 负责人: ANNE LYNCH
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-09-19
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10843725
• 关键词: 3-Dimensional; ATAC-seq; Acute Lung Injury; Address; Alveolar; Alveolar Cell Type I; Area; Benchmarking; COVID-19; COVID-19 pandemic; Cause of Death; Cell Death; Cell Differentiation process; Cell Proliferation; Cells; ChIP-seq; Chemical Injury; Chromatin; Complement; Complement Activation; Country; Data; Detection; Distal; Epigenetic Process; Epithelium; FOSB gene; Gases; Genetic Transcription; Genomic approach; Goals; Growth; Heterogeneity; In Situ; Infection; Inhalation; Injury; Intervention; Kinetics; Label; Light; Lobe; Lower Respiratory Tract Infection; Lung; Lung Adenocarcinoma; Lung diseases; Malignant neoplasm of lung; Maps; Mediating; Microscopy; Modeling; Molecular; Mus; Natural regeneration; Nature; Nuclear; Persons; Phase; Pneumonectomy; Poison; Proliferating; Recovery; Respiratory Tract Infections; Risk; Role; Running; STEM field; Sendai virus; Testing; Three-Dimensional Image; Time; Tissues; Toxin; Transcription Factor AP-1; Transcriptional Regulation; Viral; Virus Diseases; XCL1 gene; alveolar epithelium; alveolar type II cell; combat; conditional knockout; epigenetic regulation; epigenomics; epithelial injury; genetic approach; imaging approach; injured airway; injury and repair; injury burden; lung injury; lung regeneration; member; mouse model; multiple omics; novel; parainfluenza virus; pathogen; repaired; response to injury; single cell analysis; spatiotemporal; stem cell biology; stem cell function; stem cell population; stem cells; surfactant; tissue regeneration; tissue repair; training opportunity; wound healing

PROJECT SUMMARY/ABSTRACT Lower respiratory infections were the fourth leading cause of death worldwide for nearly twenty years, and in 2019 with the onset of the COVID-19 pandemic, respiratory infections quickly rose to the leading cause of death in many countries killing over 5 million people worldwide thus far. Our lungs are equipped with stem cells to help us recover from lung related injury caused by inhaling toxins and pathogens. However, like in many COVID-19 cases, the stem cells cannot always handle the injury burden. Alveolar type II (AT2) cells are facultative stem cells of the lung that secrete surfactant and aid with gas exchange. During injury, AT2 cells withdraw from homeostatic quiescence to repair damage through proliferation and differentiation into alveolar type I (AT1) cells, then revert to quiescence when the epithelium is restored. The mechanism behind AT2 cell reversible activation is unclear. To better understand this mechanism, we modeled respiratory injury in mice through a murine parainfluenza virus known as Sendai virus. Lineage tracing of AT2 cells and proliferation revealed that AT2 cells not only activate to perform in situ wound repair, but also cluster and proliferate at regions away from damage, specific to the edges of airways and vessels, as well as the most distal border of the tissue, representing de novo growth. ATAC-sequencing was performed on AT2 cells from infected mice at the peak of AT2 cell proliferation and in the recovery phase after returning to quiescence. AT2 cells gained accessibility of AP-1 motifs during injury repair and subsequently lost accessibility for AP-1 motifs at recovery. The hypothesis of this proposal is that AP-1 transcriptionally regulates AT2 cell activation to induce both in situ and de novo repair during lung injury response. We will first identify the spatiotemporal activation of AT2 cells during infection through lineage tracing AT2 cell proliferation and differentiation for detection with light sheet microscopy to generate 3D images for deciphering if the proposed in situ and de novo regions of activation are truly distinct. We will also perturb an airway stem cell population known to contribute to in situ wound repair to study region specific changes in AT2 cell activation when airway assistance is disrupted (Aim1). Second, we will investigate the regulatory mechanism in AT2 cell activation by looking at the kinetics of epigenetic change over time through injury response with bulk ATAC and single-cell mutiome-sequencing. We will also examine the role of AP-1 through AT2 cell specific conditional knockout of FOSB to examine its impact on AT2 cell activation and repair (Aim2). This study will help characterize the novel concept of in situ and de novo AT2 cell activation as well as the undiscovered epigenetic and transcriptional regulation of lung regeneration.

项目概要/摘要 近二十年来，下呼吸道感染是全球第四大死亡原因， 2019年，随着COVID-19大流行的爆发，呼吸道感染迅速上升为导致流感的主要原因 迄今为止，许多国家的死亡人数已导致全球超过 500 万人死亡。我们的肺部配备有干细胞 帮助我们从吸入毒素和病原体引起的肺部相关损伤中恢复。然而，就像许多 在 COVID-19 病例中，干细胞无法始终应对损伤负担。肺泡 II 型 (AT2) 细胞是 肺部的兼性干细胞，分泌表面活性剂并帮助气体交换。在损伤期间，AT2 细胞 退出稳态，通过增殖和分化为肺泡来修复损伤 I 型 (AT1) 细胞，然后当上皮恢复时恢复静止状态。 AT2细胞背后的机制 可逆激活尚不清楚。为了更好地理解这一机制，我们模拟了小鼠的呼吸损伤 通过一种称为仙台病毒的鼠副流感病毒。 AT2 细胞的谱系追踪和增殖 研究表明，AT2 细胞不仅可以激活进行原位伤口修复，而且可以在 远离损伤的区域，特定于气道和血管的边缘，以及最远端的边界 组织，代表从头生长。对感染小鼠的 AT2 细胞进行 ATAC 测序 AT2细胞增殖的高峰期和恢复静止后的恢复期。 AT2细胞获得 损伤修复期间 AP-1 基序的可及性，随后在恢复时失去 AP-1 基序的可及性。 该提议的假设是 AP-1 转录调节 AT2 细胞激活以诱导 肺损伤反应期间的原位修复和从头修复。我们首先要确定时空 通过谱系追踪 AT2 细胞增殖和分化，在感染期间激活 AT2 细胞 如果提议的原位和去 novo 激活区域确实不同。我们还将扰乱已知的气道干细胞群 有助于原位伤口修复，研究气道时 AT2 细胞活化的区域特异性变化 援助中断（目标 1）。其次，我们将通过以下方法研究 AT2 细胞激活的调控机制： 通过大体积 ATAC 和单细胞的损伤反应观察表观遗传随时间变化的动力学 多组测序。我们还将通过 AT2 细胞特异性条件敲除来检查 AP-1 的作用 FOSB 检查其对 AT2 细胞激活和修复的影响 (Aim2)。这项研究将有助于表征 原位和从头 AT2 细胞激活的新概念以及未被发现的表观遗传和 肺再生的转录调控。

项目成果

Microbial applications for sustainable space exploration beyond low Earth orbit.

• DOI: 10.1038/s41526-023-00285-0
• 发表时间: 2023-06-21
• 期刊: NPJ MICROGRAVITY
• 影响因子: 5.1
• 作者: Koehle, Allison P.;Brumwell, Stephanie L.;Seto, Emily P.;Lynch, Anne M.;Urbaniak, Camilla
• 通讯作者: Urbaniak, Camilla

Understanding the Complexities and Changes of the Astronaut Microbiome for Successful Long-Duration Space Missions.

• DOI: 10.3390/life12040495
• 发表时间: 2022-03-28
• 期刊: LIFE-BASEL
• 影响因子: 3.2
• 作者: Tesei, Donatella;Jewczynko, Anna;Lynch, Anne;Urbaniak, Camilla
• 通讯作者: Urbaniak, Camilla