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

项目摘要/摘要 中性粒细胞在几种常见肺部疾病的发病机制中发挥重要作用，包括 肺炎、哮喘和慢性阻塞性肺病。然而，没有针对中性粒细胞的特异疗法。 可用于治疗这些疾病。对控制中性粒细胞肺的机制有更深入的了解 炎症可能会使这种疗法的发展成为可能。 我们的团队研究了几丁质酶3-样-1(CHI3L1)，这是一种具有细胞因子样的分泌型免疫蛋白 属性。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。具体地说，我们已经证明CHI3L1抑制细胞凋亡，促进 中性粒细胞胞外陷阱(即NETase，一种促炎形式的细胞死亡)，并加重肺损伤。在……里面 在这项提议的基础上，我们试图通过四个分目标在这些初步调查结果的基础上再接再厉。首先，我们将确定 中性粒细胞上的受体，介导CHI3L1的促凋亡/抗凋亡作用。第二，我们将澄清 负责这一效应的细胞内信号通路。第三，我们将评估CHI3L1的致病性 在中性粒细胞哮喘的小鼠模型中。第四，我们将利用中性粒细胞哮喘患者的痰来 确定CHI3L1与人类疾病的相关性。成功完成这些目标将提供重要的 深入了解中性粒细胞肺部疾病的发病机制，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，为申请者准备 独立的职业生涯，作为一名内科科学家，研究肺部中性粒细胞生物学。 职业发展。为了支持这些研究和职业目标的实现，我们召集了 一支世界级的导师团队，在包括肺炎在内的每个拟议调查领域都有专业知识， 哮喘、中性粒细胞信号、网织红细胞增多症和翻译生物学。为相关课程量身定制的课程， 开展了内部会议和国家会议，以加强通过以下途径获得的培训 有指导的研究。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、丰富的国际知名 调查人员。肺、重症护理和睡眠医学科(其中拟议的研究将 发生)是坚定地致力于成功的早期职业内科医生-科学家像候选人，作为 它目前的七位K奖获得者就是明证。内科医学部也同样承诺，因为他们 在本奖项的有效期内保证75%的受保护研究时间。最后，候选人很好地- 准备执行拟议的目标，通过以下途径接受了14年的生物医学科学培训 医学-科学家和医生-科学家培训方案(MSTP和PSTP)。

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).