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

基本信息

  • 批准号:
    10449751
  • 负责人:
  • 金额:
    $ 16.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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).
项目总结/摘要 中性粒细胞在几种常见肺部疾病的发病机制中起重要作用, 肺炎、哮喘和慢性阻塞性肺病。然而,没有特定的治疗方法, 来治疗这些疾病。更深入地了解控制嗜酸性肺的机制 炎症可能使这种疗法的发展成为可能。 我们的小组研究了几丁质酶3-Like-1(Chi 3L 1),一种分泌的免疫蛋白,具有类似于大肠杆菌的活性。 特性.在使用小鼠肺炎模型的初步研究中,我们发现Chi 3L 1调节 中性粒细胞命运。具体地说,我们已经表明,Chi 3L 1抑制细胞凋亡,促进细胞凋亡的形成, 嗜中性粒细胞胞外陷阱(即NETosis,一种促炎性细胞死亡形式)和肺损伤。在 在这项建议中,我们力求通过四个次级目标,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Chi 3L 1的促神经元凋亡/抗凋亡作用。第二,我们将阐明 细胞内的信号传导途径负责这种效果。第三,评估Chi 3L 1的致病性。 在嗜肺性哮喘小鼠模型中。第四,我们将使用嗜肺性哮喘患者的痰液, 建立Chi 3L 1在人类疾病中的相关性。这些目标的成功实现将提供重要的 深入了解嗜酸性肺病的发病机制,并帮助确定新的治疗策略, 了以下条件这项研究还将提供一个严格的培训计划,以准备申请人 作为一名研究肺部中性粒细胞生物学的医生科学家的独立职业。 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 一个世界级的导师团队,他们在包括肺炎在内的每个拟议调查领域都具有专业知识, 哮喘、中性粒细胞信号传导、NETosis和翻译生物学。量身定制的相关课程, 内部会议和国家会议,以加强通过以下途径获得的培训: 指导研究。环境耶鲁大学医学院代表了这项工作的理想环境,因为它 合作氛围,尖端的技术设施,以及丰富的国际知名 investigators.肺科,重症监护和睡眠医学(其中拟议的研究将 发生)是深深致力于成功的早期职业医生,科学家喜欢的候选人,因为 其目前的七个K获奖者证明。内科也同样如此,因为他们 在此奖项期间,保证75%的研究时间受到保护。最后,候选人很好- 准备执行拟议的目标,接受了14年的生物医学科学培训,通过 医学科学家和医生科学家培训计划(MSTP和PSTP)。

项目成果

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SAMIR GAUTAM其他文献

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{{ truncateString('SAMIR GAUTAM', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 16.61万
  • 项目类别:

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