CLEC-2/Pdpn Mediated Regulation of Airway Inflammation

 描述（由申请人提供）：哮喘是一种高度流行的气道炎症性疾病，可导致严重的支气管收缩和呼吸衰竭。大约10%的患者患有严重的、持续的、难以控制的哮喘，特别是那些患有白细胞介素（IL）-17介导的、嗜酸性气道炎症的患者，无论是单独的还是与2型炎症联合的。不幸的是，嗜酸性哮喘患者对目前的治疗反应不佳，包括目前哮喘治疗的支柱，皮质类固醇，突出了识别能够调节2型和17型反应的分子靶点的重要性。 我们最近确定podoplanin（Pdpn），表面糖蛋白优先表达的Th 17细胞，作为一种新的负调节效应CD 4 T细胞反应。重要的是，我们的初步研究表明，缺乏C型凝集素样受体-2（CLEC-2）（树突状细胞（DC）上表达的Pdpn配体）的小鼠会发生自发性气道炎症，其特征是浸润肺部的Th 2和Th 17细胞增加。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两种细胞类型的双向调节，并且对于控制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驻留CLEC-2+抗原呈递细胞类型，分析CLEC-2在调节这些细胞功能中的作用，并使用基于网络的转录组学方法来鉴定由CLEC-2信号控制的关键免疫调节回路来研究这一假设。此外，我们建议研究CLEC-2在DC上的表达通过影响效应CD 4 T细胞分化、调节调节性T细胞的功能、调节2型和17型免疫应答的机制。 细胞，并影响肺固有淋巴样细胞（ILC），特别是通过使用单细胞转录组学方法来鉴定ILC功能的关键调节因子。 在我的导师Vijay Kuchroo博士的指导下，我制定了一个为期五年的培训计划，提供成为一名独立的医生科学家所需的技术和教学培训，专注于研究肺部炎症的免疫调节途径。重要的是，该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组学分析方面的专业知识，这是该提案的两个关键领域。因此，这项建议将提供培训和科学基础， 以实现我的最终目标，成为一名独立资助的医生科学家，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.