Decoding temporal epithelial signaling programs to restore homeostasis in acute lung injury

解码颞上皮信号传导程序以恢复急性肺损伤的稳态

• 批准号: 10297749
• 负责人: John G. Albeck
• 金额: $ 59.34万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297749
• 关键词: Accounting; Acute Lung Injury; Adult Respiratory Distress Syndrome; Airway Disease; Alveolar; Benchmarking; Biological Models; COVID-19; Caring; Cell Signaling Process; Cell physiology; Cells; Cellular biology; Chronic Obstructive Airway Disease; Communication; Complement; Complex; Computer Models; Cytokine Signaling; Data; Disease; Epithelial; Epithelial Cells; Event; FRAP1 gene; Failure; Fibrosis; Homeostasis; Image; Immune; Immune response; Immunofluorescence Immunologic; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Intervention; Link; Lung; Lung Inflammation; Lung diseases; MAP Kinase Gene; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measurement; Metabolic; Methodology; Methods; Modeling; Modernization; NF-kappa B; Output; Paracrine Communication; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Play; Population; Process; Production; Proto-Oncogene Proteins c-akt; Resolution; Respiratory Tract Infections; Role; Route; Sentinel; Signal Pathway; Signal Transduction; Source; Specific qualifier value; Structure; Syndrome; System; Technology; Time; Tissues; Variant; Work; airway epithelium; biological adaptation to stress; cell behavior; cell growth; cell type; cytokine; data mining; drug efficacy; improved; inflammatory milieu; kinase inhibitor; live cell imaging; mortality; multidisciplinary; new technology; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; programs; respiratory; response; sensor; spatial relationship; stem; tool; transcription factor

Abstract Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common pulmonary syndrome with high mortality. ALI/ARDS stems from a communication breakdown between lung epithelial cells and immune cells and is a major factor in severe cases of respiratory infection, including COVID-19. Treatments for ALI/ARDS are currently limited by inadequate models of the complex relationships between signaling pathways and lung epithelial cell behavior. A core network of signaling pathways control epithelial structure and cytokine release and are an important unexploited point of intervention in ALI/ARDS via existing targeted kinase inhibitors or metabolic modulators. This core network includes NF-kB, a primary transcription factor for cytokine release and inflammation, and the kinases ERK, AKT, JNK, p38, mTOR and AMPK, which modulate cytokine production in response to cellular growth and metabolic status. Notably, this signaling network also plays a causal role in lung cancer and is involved in other diseases of the lung epithelium, including fibrosis and COPD. Our lab has developed an extensive live-cell technology platform for tracking temporal programs of signaling events – different patterns of timing, intensity, and coordination between these pathways – that govern epithelial cell fate decisions. Our overall objective is to quantitatively decode how cytokine secretion is specified by multi-kinase activity programs. Our hypothesis is that accounting for coinciding phases of signaling activity at the single cell level will significantly improve the prediction of both overall and local variability in cytokine secretion and will identify metabolic manipulations that reduce inflammation. Our approach will develop the technology needed to detect and manipulate temporal signaling programs to restore lung epithelial homeostasis in ALI/ARDS. Aim 1 will develop a high-content data-driven model correlating signaling programs to cytokine release on a cell-by-cell basis across multiple conditions. Aim 2 will develop the capacity to characterize the localized inflammatory environment in subregions of lung epithelium by examining the dynamic programs of kinase signaling in groups of 10-100 neighboring cells. In the process, we will provide proof of principle for using panels of fixed immunofluorescence markers to capture dynamic signaling patterns. Aim 3 will investigate the potential for manipulating temporal signaling programs with existing pharmacological agents, focusing on the emerging benefits of AMPK activators as a route to modulate the larger signaling network. Our multi-disciplinary team will work across the boundaries of pulmonary care, cell biology, and computational systems modeling to create a technology platform that connects modern single- cell signal transduction analysis to pressing challenges in lung disease. We anticipate that our project will identify potential new routes of intervention for ALI/ARDS, as well as revealing general concepts in cytokine signaling pathways that are broadly relevant for the treatment of lung malignancies and inflammatory disease.

抽象的 急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是一种常见的肺部疾病 高死亡率的 ALI/ARDS 源于肺之间的通讯故障。 上皮细胞和免疫细胞，是呼吸道感染严重病例的主要因素， 包括 COVID-19 在内的 ALI/ARDS 治疗目前因模型不足而受到限制。 信号通路与肺上皮细胞行为之间的复杂关系是核心。 信号通路网络控制上皮结构和细胞因子释放，是 通过现有的靶向激酶抑制剂对 ALI/ARDS 进行重要的未开发干预点或 该核心网络包括 NF-kB，一种主要转录因子。 细胞因子释放和炎症，以及激酶 ERK、AKT、JNK、p38、mTOR 和 AMPK， 它根据细胞生长和代谢状态调节细胞因子的产生。 值得注意的是，该信号网络还在肺癌中发挥因果作用，并参与其他疾病 肺上皮疾病，包括纤维化和慢性阻塞性肺病（COPD）。 用于跟踪信号事件时间程序的广泛活细胞技术平台 – 这些途径之间的时间安排、强度和协调的不同模式——控制着 我们的总体目标是定量解码细胞因子如何决定。 分泌是由多激酶活性程序指定的。 单细胞水平上信号活动的重合阶段将显着改善 预测细胞因子分泌的整体和局部变异性，并识别代谢 我们的方法将开发减少炎症所需的技术。 检测和操纵时间信号程序以恢复肺上皮稳态 ALI/ARDS。目标 1 将开发一个关联信号程序的高内容数据驱动模型。 目标 2 将开发在多种条件下逐个细胞释放细胞因子的方法。 表征肺上皮亚区域局部炎症环境的能力 通过检查 10-100 个相邻细胞组中激酶信号传导的动态程序。 在此过程中，我们将提供使用固定免疫荧光面板的原理证明 目标 3 将研究捕获动态信号传导模式的标记。 用现有的药物制剂操纵时间信号程序，重点关注 AMPK 激活剂作为调节更大信号网络的途径的新优势。 多学科团队将跨越肺部护理、细胞生物学和 计算系统建模创建一个连接现代单机的技术平台 细胞信号转导分析应对肺部疾病的紧迫挑战。 项目将确定 ALI/ARDS 的潜在新干预途径，并揭示 与治疗广泛相关的细胞因子信号传导途径的一般概念 肺部恶性肿瘤和炎症性疾病。