Cellular crosstalk in the maintenance of lung epithelial homeostasis

维持肺上皮稳态中的细胞串扰

• 批准号: 10431768
• 负责人: Daniel Thomas Montoro
• 金额: $ 6.64万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431768
• 关键词: Adherens Junction; Anatomy; Apical; Asthma; Biological; Biological Assay; Blocking Antibodies; C Type Lectin Receptors; Cells; Chronic Obstructive Airway Disease; Data; Development; Disease; Epithelial; Epithelial Cells; Extrinsic asthma; Genetic; Genomics; Goals; Homeostasis; Hospitals; Immune; Immune response; In Situ; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Institutes; Life; Ligands; Link; Lung; Lung Inflammation; Lung diseases; Lymphatic; Maintenance; Maps; Mediating; Mentorship; Molecular; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Mus; Pathway interactions; Pattern; Predisposition; Process; Production; Regulation; Role; Scientist; Severities; Testing; Time; Tissues; Training; Tumor-infiltrating immune cells; Woman; Work; airway epithelium; airway hyperresponsiveness; airway inflammation; cell type; cytokine; eosinophil; in vivo; interest; mouse genetics; new therapeutic target; novel; particle; pathogen; pedagogy; podoplanin; prevent; protective effect; pulmonary function; receptor; recruit; restoration; single-cell RNA sequencing; therapeutic target

Project summary Lung function is essential to sustain life and depends on the continuous neutralization of inhaled pathogens, particles, and noxious substances. The mucosal epithelial barrier of the lung is the first line of defense against contaminants. In the case of a compromised mucosal epithelial barrier, epithelial alarmins recruit inflammatory responses to neutralize threats and aid in the restoration of lung homeostasis. The mechanisms that regulate inflammation must accommodate sensitivity to pathogens while preventing excessive inflammation that results in further epithelial damage. That excessive inflammation is a defining feature of major lung diseases like asthma and COPD underscores the need for regulatory mechanisms that safeguard the lung against excessive inflammation. The interaction between receptor C-type lectin-like 2 (Clec-2) and its ligand Podoplanin (Pdpn) has been found to regulate inflammatory responses in various tissues. We found that both Clec-2-deficiency and Pdpn- deficiency cause spontaneous lung inflammation and asthma-like disease in mice. Specific blocking of Clec- 2/Pdpn interaction increases the epithelial production of alarmins and the susceptibility to allergic asthma. Taken together, we hypothesize that Clec-2/Pdpn crosstalk is a mechanism that, when intact, resists inflammation and promotes lung homeostasis. We propose to exploit single-cell genomics to identify all of the cell types and subsets that express Clec-2 and Pdpn, and to spatially map them over the lung's anatomy. In so doing, we will identify putative cellular circuits that mediate Clec-2/Pdpn interactions, and test these circuits using in vivo mouse genetics. Finally, we propose to investigate the cellular mechanisms that link Clec-2/Pdpn crosstalk to the regulation of epithelial alarmins and lung inflammation. Overall, we will use Clec-2/Pdpn interactions as an entry point to exploring the cellular circuits and molecular mechanisms that safeguard lung homeostasis, with the goal to identify new therapeutic targets for inflammatory diseases. My ultimate training goal is to become an independent scientist focusing on cellular circuits that support lung function and that are dysregulated in disease. With the guidance and mentorship of Dr. Aviv Regev at the Broad Institute and Dr. Vijay Kuchroo at Brigham and Women's Hospital, I composed a training plan that will provide me the essential technical and pedagogical training to successfully advance my training goals.

项目概要 肺功能对于维持生命至关重要，并取决于吸入病原体的持续中和， 颗粒和有毒物质。肺的粘膜上皮屏障是抵抗病毒的第一道防线 污染物。在粘膜上皮屏障受损的情况下，上皮警报素会招募炎症 消除威胁并帮助恢复肺稳态的反应。调节机制 炎症必须适应对病原体的敏感性，同时防止导致过度炎症 进一步造成上皮损伤。过度炎症是主要肺部疾病的一个决定性特征，例如 哮喘和慢性阻塞性肺病强调需要保护肺部免受过度侵害的监管机制 炎。 发现受体 C 型凝集素样 2 (Clec-2) 与其配体 Podoplanin (Pdpn) 之间的相互作用 调节各种组织的炎症反应。我们发现 Clec-2 缺陷和 Pdpn- 缺乏会导致小鼠自发性肺部炎症和哮喘样疾病。特定阻断 Clec- 2/Pdpn 相互作用会增加上皮警报素的产生以及对过敏性哮喘的易感性。 综上所述，我们假设 Clec-2/Pdpn 串扰是一种在完好无损时抵抗的机制 炎症并促进肺稳态。我们建议利用单细胞基因组学来识别所有 表达 Clec-2 和 Pdpn 的细胞类型和亚群，并将它们在肺部解剖结构上进行空间映射。在这样 这样做，我们将确定介导 Clec-2/Pdpn 相互作用的假定细胞回路，并测试这些回路 使用体内小鼠遗传学。最后，我们建议研究连接 Clec-2/Pdpn 的细胞机制 上皮警报素和肺部炎症调节的串扰。总的来说，我们将使用 Clec-2/Pdpn 相互作用作为探索保护肺的细胞回路和分子机制的切入点 稳态，目标是确定炎症性疾病的新治疗靶点。 我的最终培训目标是成为一名独立科学家，专注于支持肺的细胞回路 功能和疾病中失调。在 Aviv Regev 博士的指导和指导下 布罗德研究所和布莱根妇女医院的 Vijay Kuchroo 博士，我制定了一个培训计划，该计划将 为我提供必要的技术和教学培训，以成功推进我的培训目标。