CLEC-2/Pdpn Mediated Regulation of Airway Inflammation

 描述(申请人提供)：哮喘是一种高度流行的呼吸道炎症性疾病，可导致严重的支气管收缩和呼吸衰竭。约10%的患者患有严重的、持续性的、难以控制的哮喘，特别是那些由白细胞介素17(IL-17)介导的中性粒细胞呼吸道炎症，无论是单独还是合并2型炎症。不幸的是，中性粒细胞哮喘患者对目前的治疗方法反应不佳，包括目前哮喘治疗的主流激素皮质类固醇，这突显了确定能够调节2型和17型反应的分子靶点的重要性。 Pdpn是一种由Th17细胞优先表达的表面糖蛋白，我们最近发现它是一种新的效应CD4T细胞反应的负性调节因子。重要的是，我们的初步研究表明，缺乏表达在树突状细胞(DC)上的Pdpn配体C型凝集素样受体-2(CLEC-2)的小鼠会发生自发性的呼吸道炎症，其特征是Th2和Th17细胞都增加了对肺的渗透。因此，我们假设Pdpn+T细胞和CLEC-2+树突状细胞之间的相互作用导致这两种细胞类型的双向调节，并对控制2型和17型介导的气道炎症至关重要。我们建议通过鉴定肺部驻留的CLEC-2+抗原提呈细胞类型，分析CLEC-2在调节这些细胞功能中的作用，以及使用基于网络的转录方法来识别由CLEC-2信号控制的关键免疫调节电路来研究这一假说。此外，我们建议研究DC上CLEC-2的表达通过影响效应器CD4T细胞分化，调节调节性T细胞的功能来调节2型和17型免疫反应的机制 主要是通过使用单细胞转译方法来确定ILC功能的关键调节因子。 在我的导师维贾伊·库奇鲁博士的指导下，我制定了一个为期五年的培训计划，提供所需的技术和教学培训，以成为一名专注于研究肺部炎症的免疫调节途径的独立内科科学家。重要的是，这个项目将由一个科学咨询委员会监督，该委员会提供肺部炎症研究和免疫细胞转录分析方面的专业知识，这是该提案的两个关键领域。因此，该提案将提供培训和科学基础。 为了实现我的最终目标，成为一名独立资助的内科科学家，研究调节免疫介导的肺部疾病的途径。

 DESCRIPTION (provided by applicant): Asthma is a highly prevalent inflammatory disorder of the airways that can lead to severe bronchoconstriction and respiratory failure. About 10% of patients have severe, persistent, difficult to control asthma, particularly those with interleukin (IL)-17-mediated, neutrophilic airway inflammation either alone or in conjunction with type 2 inflammation. Unfortunately, patients with neutrophilic asthma respond poorly to current therapies, including the mainstay of current asthma therapy, corticosteroids, highlighting the importance of identifying molecular targets capable of regulating both type 2 and type 17 responses. We recently identified podoplanin (Pdpn), a surface glycoprotein preferentially expressed by Th17 cells, as a novel negative regulator of effector CD4 T cell responses. Importantly, our preliminarily studies show that mice lacking C-type Lectin-like Receptor-2 (CLEC-2), a Pdpn ligand expressed on dendritic cells (DCs), develop spontaneous airway inflammation marked by an increase in both Th2 and Th17 cells infiltrating the lung. We therefore hypothesize that interactions between Pdpn+ T cells and CLEC-2+ dendritic cells result in bidirectional regulation of both cell types and are critical for controlling both type 2- and type 17-mediated airway inflammation. We propose to investigate this hypothesis by identifying lung resident CLEC-2+ antigen presenting cell types, analyzing the role of CLEC-2 in regulating the function of those cells, and using a network-based, transcriptomic approach to identify key immunoregulatory circuits controlled by CLEC-2 signaling. Furthermore, we propose to investigate the mechanisms by which CLEC-2 expression on DCs regulates type 2 and type 17 immune responses by affecting effector CD4 T cell differentiation, modulating the function of regulatory T cells, and affecting lung resident innate lymphoid cells (ILCs), notably through the use of single cell trancriptomic approaches to identify key regulators of ILC function. With the guidance of my mentor, Dr. Vijay Kuchroo, I have developed a five-year training program to provide both the technical and didactic training needed to become an independent physician-scientist focused on studying immunoregulatory pathways in lung inflammation. Importantly, this project will be overseen by a scientific advisory committee providing expertise in the study of pulmonary inflammation and the transcriptomic analysis of immune cells, two key areas of this proposal. This proposal will therefore provide the training and scientific foundation to achieve my ultimate goal of becoming an independently funded physician-scientist investigating pathways regulating immune-mediated lung disease.