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: 10616790
• 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/10616790
• 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; Inhibition of Apoptosis; Injury; Internal Medicine; International; Investigation; Laboratory Study; Lectin; Link; Lung; Lung diseases; Lytic; MAP Kinase Gene; Macrophage; Maps; Mediating; Medical; Medicine; Mentors; Mentorship; Modeling; Mus; Outcome; PIK3CG gene; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; 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; Technology; 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; medical schools; meetings; mouse model; neutrophil; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; phosphoproteomics; physician-scientist training program; 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).

项目概要/摘要 中性粒细胞在几种常见肺部疾病的发病机制中发挥着重要作用，包括 肺炎、哮喘和慢性阻塞性肺病。然而，尚无中性粒细胞特异性疗法 可用于治疗这些病症。更深入地了解控制中性粒细胞肺的机制 炎症可能有助于开发此类疗法。 我们的小组研究了几丁质酶 3-Like-1 (Chi3L1)，一种具有细胞因子样作用的分泌性免疫蛋白 特性。在使用小鼠肺炎模型的初步研究中，我们发现 Chi3L1 调节 中性粒细胞的命运。具体来说，我们已经证明 Chi3L1 抑制细胞凋亡，促进形成 中性粒细胞胞外陷阱（即 NETosis，细胞死亡的促炎形式），并加重肺损伤。在 在这项提案中，我们力求通过四个分目标以这些初步调查结果为基础。首先，我们将确定 中性粒细胞上的受体介导 Chi3L1 的促 NETotic/抗凋亡作用。其次，我们要阐明 负责这种作用的细胞内信号传导途径。第三，我们将评估Chi3L1的致病性 在中性粒细胞性哮喘小鼠模型中。第四，我们将使用中性粒细胞性哮喘患者的痰液来 确定 Chi3L1 在人类疾病中的相关性。成功完成这些目标将提供重要的 深入了解中性粒细胞性肺部疾病的发病机制，并有助于确定新的治疗策略 这些条件。这项研究还将提供严格的培训计划，帮助申请人做好准备 作为一名研究肺部中性粒细胞生物学的医师科学家的独立职业。 职业发展。为了支持这些研究和职业目标的实现，我们聚集了 世界一流的导师团队，在每个拟议的研究领域（包括肺炎）拥有专业知识， 哮喘、中性粒细胞信号传导、NETosis 和转化生物学。相关课程的定制课程， 召开了校内会议和全国会议，以加强通过以下方式获得的培训： 指导研究。环境。耶鲁大学医学院是这项工作的理想环境，因为它 协作氛围、尖端技术设施和丰富的国际知名资源 调查人员。肺科、重症监护和睡眠医学科（其中拟议的研究将 发生）坚定地致力于像候选人这样的早期职业医师科学家的成功，因为 目前七位 K 获奖者就是明证。内科也有同样的承诺，因为他们 保证在该奖项期间有 75% 的受保护研究时间。最后，候选人很好—— 准备好执行拟议的目标，接受了十四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）。

项目成果

Prevalence and treatment of postobstructive pneumonia among older adults with advanced cancer.

患有晚期癌症的老年人中阻塞性肺炎的患病率和治疗。

• 发表时间: 2022
• 作者: Lee, Seohyuk;O'Donovan, Lisa;Cohen, Avi J;Gautam, Samir;Quagliarello, Vincent;Juthani-Mehta, Manisha;Datta, Rupak
• 通讯作者: Datta, Rupak