Chitinase 3-like-1 regulates neutrophil cell fate in inflammatory lung disease

几丁质酶 3-like-1 调节炎症性肺病中性粒细胞的命运

• 批准号: 10449751
• 负责人: SAMIR GAUTAM
• 金额: $ 16.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449751
• 关键词: Achievement; Acute; Acute Respiratory Distress Syndrome; Apoptosis; Apoptotic; Area; Asthma; Award; Biology; CHI3L1 gene; Cell Death; Cells; Cellular Assay; Chemicals; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Critical Care; Cystic Fibrosis; Development; Disease; Disease model; Educational Curriculum; Environment; Goals; Human; Immune; Immunology; Impairment; Inflammation; Inflammatory; Injury; Internal Medicine; International; Investigation; Laboratory Study; Lectin; Link; Lung; Lung diseases; Lytic; MAP Kinase Gene; Maps; Mediating; Medical; Medicine; Mentors; Mentorship; Modeling; Mus; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physicians; Play; Pneumonia; Property; Proteins; Pulmonary Inflammation; Recombinants; Research; Research Personnel; Resolution; Respiratory Disease; Role; Science; Scientist; Severities; Severity of illness; Signal Pathway; Signal Transduction; Sleep; Sputum; System; Testing; Time; Training; Training Programs; Work; asthmatic; career; career development; cell type; collaborative environment; cytokine; extracellular; human disease; in vitro Assay; in vitro testing; in vivo; inflammatory lung disease; inhibitor; insight; kinase inhibitor; lung injury; macrophage; medical schools; meetings; mouse model; neutrophil; new therapeutic target; novel; novel therapeutic intervention; phosphoproteomics; pneumonia model; prevent; receptor; recruit; response; success; symposium; targeted treatment; theories; tissue injury

PROJECT SUMMARY/ABSTRACT Neutrophils play an important role in the pathogenesis of several common lung diseases including pneumonia, asthma, and chronic obstructive pulmonary disease. Yet, no neutrophil-specific therapies are available to treat these conditions. A deeper understanding of the mechanisms that control neutrophilic lung inflammation may enable development of such therapies. Our group investigates chitinase 3-Like-1 (Chi3L1), a secreted immune protein with cytokine-like properties. In preliminary studies using a murine pneumonia model, we have found that Chi3L1 regulates neutrophil cell fate. Specifically, we have shown that Chi3L1 suppresses apoptosis, promotes formation of neutrophil extracellular traps (i.e. NETosis, a pro-inflammatory form of cell death), and worsens lung injury. In this proposal, we seek to build upon these preliminary findings through four sub-aims. First, we will identify the receptor on neutrophils that mediates the pro-NETotic/anti-apoptotic effect of Chi3L1. Second, we will elucidate the intracellular signaling pathways responsible for this effect. Third, we will assess the pathogenicity of Chi3L1 in a murine model of neutrophilic asthma. Fourth, we will use sputum from patients with neutrophilic asthma to establish the relevance of Chi3L1 in human disease. Successful completion of these aims will provide important insight into the pathogenesis of neutrophilic lung diseases and help to identify new therapeutic strategies for these conditions. This research will also provide a rigorous training program to prepare the applicant for an independent career as a physician-scientist studying neutrophil biology in the lung. Career Development. To support achievement of these research and career goals, we have assembled a world-class team of mentors with expertise in each proposed area of investigation including pneumonia, asthma, neutrophil signaling, NETosis, and translational biology. A tailored curriculum of relevant coursework, intramural meetings, and national conferences has been developed to reinforce the training gained through mentored research. Environment. Yale School of Medicine represents an ideal setting for this work given its collaborative atmosphere, cutting-edge technological facilities, and abundance of internationally-renowned investigators. The Section of Pulmonary, Critical Care and Sleep Medicine (wherein the proposed research will take place) is deeply committed to the success of early career physician-scientists like the candidate, as evidenced by its seven current K awardees. The Department of Internal Medicine is similarly committed, as they have guaranteed 75% protected research time for the duration of this award. Finally, the candidate is well- prepared to execute the proposed aims, having received fourteen years of training in biomedical science through Medical-Scientist and Physician-Scientist Training Programs (MSTP and PSTP).

项目摘要/摘要 中性粒细胞在几种常见肺部疾病的发病机理中起着重要作用 肺炎，哮喘和慢性阻塞性肺部疾病。然而，没有中性粒细胞特异性疗法 可用于治疗这些情况。对控制嗜中性肺的机制有更深入的了解 炎症可能会导致这种疗法的发展。 我们的小组研究了几丁质酶3-like-1（CHI3L1），一种分泌的免疫蛋白，具有细胞因子样 特性。在使用鼠肺炎模型的初步研究中，我们发现CHI3L1调节 中性粒细胞命运。具体而言，我们已经表明CHI3L1抑制凋亡，促进 中性粒细胞外陷阱（即Netosis，一种细胞死亡的促炎形式），并使肺部损伤恶化。在 这项提议，我们试图通过四个子艾姆（Sub-aims）建立这些初步发现。首先，我们将确定 嗜中性粒细胞的受体介导CHI3L1的促纽/抗凋亡作用。其次，我们将阐明 细胞内信号传导途径负责这种效果。第三，我们将评估CHI3L1的致病性 在中性粒细胞性哮喘的鼠模型中。第四，我们将使用嗜中性哮喘患者的痰液 确定Chi3L1在人类疾病中的相关性。这些目标成功完成将提供重要的 深入了解嗜中性肺疾病的发病机理，并有助于确定新的治疗策略 这些条件。这项研究还将提供一项严格的培训计划，以准备申请人 作为医生科学家研究中性粒细胞生物学的独立职业。 职业发展。为了支持这些研究和职业目标的实现，我们已经组装了 一个世界一流的导师团队，在每个提议的调查领域都具有专业知识，包括肺炎， 哮喘，嗜中性粒细胞信号传导，肠病和转化生物学。相关课程的量身定制课程， 已经开发了壁上会议和民族会议，以加强通过 指导的研究。环境。耶鲁大学医学院代表了这项工作的理想环境 协作氛围，尖端的技术设施和丰富的国际知名度 调查人员。肺，重症监护和睡眠医学的一部分（拟议的研究将在其中 发生的）非常致力于早期职业医生等候选人的成功， 目前的七个K获奖者证明了这一点。内科系也同样承诺 在此奖项期间，保证了75％的保护时间。最后，候选人很好 准备执行拟议的目标，并通过14年的生物医学科学培训 医学科学家和医师科学家培训计划（MSTP和PSTP）。