Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury

靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生

• 批准号: 10396637
• 负责人: Ann Marie Pendergast
• 金额: $ 51.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396637
• 关键词: 3-Dimensional; Acute; Acute Lung Injury; Air; Alveolar; Alveolar Cell; Architecture; Bacterial Infections; Bacterial Pneumonia; Basal Cell; Biochemical; Biological Assay; Cell Proliferation; Cells; Clinical effectiveness; Coculture Techniques; Complement; Coupled; DNA Damage; Data; Differentiation Antigens; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Genetic; Hypoxia; Hypoxia Inducible Factor; Inflammation; Injury; Liquid substance; Lung; Lung Adenocarcinoma; Lung Neoplasms; Mediating; Modeling; Mus; Natural regeneration; Nature; Organoids; Pathologic; Pathway interactions; Pharmacology; Phosphotransferases; Play; Population; Proliferating; Regulation; Reporting; Residual state; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Solid Neoplasm; Stimulus; Stress; Time; Tissues; Transcription Coactivator; Tyrosine Phosphorylation; airway epithelium; airway regeneration; alveolar epithelium; bronchial epithelium; cell injury; cell motility; cell regeneration; cell type; chemotherapy; effectiveness evaluation; epithelial stem cell; epithelium regeneration; hypoxia inducible factor 1; in vivo; inhibitor; injured airway; injury and repair; insight; leukemia; loss of function; mouse model; novel; pathogen; pneumonia model; progenitor; regeneration following injury; repaired; response; response to injury; stem cell proliferation; stem cells; therapeutic target; transcription factor; tumor; tumorigenesis

ABSTRACT Tyrosine phosphorylation networks have been implicated in the regulation of epithelial cell plasticity, which is often induced by injury in multiple tissue types. Regeneration following injury is mediated by dynamic intercellular signaling among diverse epithelial progenitor cell populations and residual cells. Recent studies have revealed a significant role for cell plasticity mechanisms induced by injury where cells from one region contribute to repair of another region after severe and acute damage. Despite the identification of multiple region-specific progenitor cells activated following injury, the identity of molecules that might be therapeutically targeted in response to injury to promote activation of progenitor cell types has remained elusive. We recently showed that Abl kinases are highly activated in bronchial epithelial cells in response to pathogen-induced injury, and that Abl inactivation in a subpopulation of airway cells promotes intercellular signaling among lung epithelial cell progenitors to induce alveolar regeneration after bacterial pneumonia challenge. Further, we have recently found that inhibition of Abl kinases after airway damage induced by toxic agents (SO2 exposure) promotes basal cell proliferation and enhances differentiation. Together these data reveal for the first time a role for Abl kinases in regeneration of both the alveolar and airway epithelium after injury by pathogens and toxic agents. The overall hypothesis is that activation of the Abl kinases in response to injury promotes lung epithelial damage, and that Abl inactivation in lung epithelial progenitors promotes efficient and rapid regeneration and re-establishment of tissue architecture following injury. The specific aims are: 1. Evaluate the role of Abl kinases in the regulation of alveolar epithelium regeneration in response to pathogen-induced injury. To this end we will: A) evaluate the role of Abl kinases in alveolar regeneration in response to acute lung injury and assess the effectiveness of Abl inhibitors to enhance both residual progenitor cell proliferation as well as invoking plasticity of airway progenitors for efficient and rapid alveolar regeneration; and B) assess whether Abl1 targets the HIF1 transcription factor in response to alveolar injury and repair. 2. Define the Abl-dependent pathways implicated in airway epithelium regeneration. In this aim, we will A) evaluate whether Abl kinases modulate the response of the airway epithelium during injury and whether Abl inactivation functions to promote airway regeneration required to restore airway epithelial architecture and function; and B) identify Abl-regulated pathways altered in the regenerating airway epithelium and evaluate the role of selected Abl targets including Yap1 in the regulation of airway epithelial cell proliferation, differentiation, and survival after injury. These studies break new ground as they will define novel Abl-regulated pathways activated in response to injury and identify epithelial progenitors with enhanced cell plasticity in response to Abl inactivation, leading to regeneration of the lung epithelium.

抽象的 酪氨酸磷酸化网络已在上皮细胞可塑性的调节中隐含 经常在多种组织类型中受伤引起。受伤后的再生是通过动态介导的 潜水员上皮祖细胞群和残留细胞之间的细胞间信号传导。最近的研究 已经揭示了受损伤引起的细胞可塑性机制的重要作用，其中一个区域的细胞 在严重和急性损坏后促进另一个区域的修复。尽管确定了多个 损伤后激活的区域特异性祖细胞，可能是热的分子的身份 响应损伤以促进祖细胞类型的激活的针对性仍然难以捉摸。我们最近 结果表明，由于病原体诱导的损伤，ABL激酶在支气管上皮细胞中被高度激活， 并且气道细胞亚群中的灭活促进了肺上皮之间的细胞间信号传导 细胞祖细胞在肺炎挑战后诱导肺泡再生。此外，我们最近有 发现在有毒剂引起的气道损伤后抑制ABL激酶（SO2暴露）会促进 基本细胞增殖并增强分化。这些数据共同揭示了ABL的角色 病原体和有毒药物损伤后牙槽和气道上皮再生的激酶。 总体假设是，响应损伤的ABL激酶的激活促进了肺上皮 损害，并且肺上皮祖细胞中的灭活促进了有效而快速再生和 受伤后的组织结构重新建立。具体目的是：1。评估ABL激酶的作用 在调节肺泡上皮再生中，响应病原体诱导的损伤。为此，我们 将：a）评估ABL激酶在急性肺损伤和评估中的作用 ABL抑制剂可以增强残留祖细胞增殖和调用的有效性 气道祖细胞的可塑性，以实现高效和快速的肺泡再生； b）评估ABL1是否目标 HIF1转录因子响应肺泡损伤和修复。 2。定义ABL依赖性途径 在气道上皮再生中实施。在此目标中，我们将a）评估ABL激酶是否调节 受伤期间气道上皮的响应以及射精灭活是否功能促进气道 恢复气道上皮架构和功能所需的再生； b）确定ABL调节 途径改变了再生气道上皮，并评估了选定的ABL目标的作用 YAP1在气道上皮细胞增殖，分化和受伤后生存中。这些 研究破裂了新的基础，因为它们将定义新的ABL调节途径，以应对伤害和 鉴定上皮祖细胞具有增强的细胞可塑性，以响应ABL灭活，导致 肺上皮的再生。