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.

项目摘要 肺功能对于维持生命至关重要，取决于吸入病原体的连续中和， 颗粒和有害物质。肺的粘膜上皮屏障是对抗的第一道防线 污染物。如果粘膜上皮屏障受损，上皮警报素会募集炎症 对中和威胁的反应并有助于恢复肺稳态。调节的机制 炎症必须适应对病原体的敏感性，同时防止过度炎症 进一步的上皮损害。过度炎症是主要肺部疾病的一个定义特征 哮喘和COPD强调了需要保护肺部过度的调节机制 炎。 已经发现了受体C型凝集素样2（CLEC-2）及其配体Podoplanin（PDPN）之间的相互作用 调节各种组织中的炎症反应。我们发现CLEC-2缺陷和PDPN- 缺乏会导致小鼠自发的肺部炎症和类似哮喘的疾病。特异性块 - 2/PDPN相互作用增加了警报蛋白的上皮产生和对过敏性哮喘的敏感性。 两者合计，我们假设CLEC-2/PDPN串扰是一种机制，当完整时， 炎症并促进肺稳态。我们建议利用单细胞基因组学以识别所有 表达CLEC-2和PDPN的细胞类型和子集，并在肺部的解剖结构上进行空间绘制它们。在这样 这样做，我们将确定介导CLEC-2/PDPN相互作用的推定的细胞电路，并测试这些电路 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 串扰上皮警报器和肺部炎症的调节。总体而言，我们将使用CLEC-2/PDPN 相互作用是探索保护肺的细胞回路和分子机制的切入点 稳态，目的是确定炎症性疾病的新治疗靶标。 我的最终培训目标是成为一名专注于支持肺部的细胞电路的独立科学家 功能且在疾病中失调。在Aviv Regev博士的指导和指导下 Broad Institute和Brigham和妇女医院的Vijay Kuchroo博士，我制定了一个培训计划 为我提供基本的技术和教学培训，以成功地提高我的培训目标。