CLEC-2/Pdpn Mediated Regulation of Airway Inflammation

CLEC-2/Pdpn 介导的气道炎症调节

• 批准号: 9087495
• 负责人: Patrick Ryland Burkett
• 金额: $ 18.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-11 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087495
• 关键词: Adrenal Cortex Hormones; Adult; Advisory Committees; Affect; Alleles; Antigen-Presenting Cells; Area; Asthma; Biological Markers; Bronchoconstriction; C-Type Lectins; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Dendritic Cells; Disease; Foundations; Frequencies; Funding; Goals; Immune; Immune response; Immunologics; In Vitro; Inflammation; Inflammatory; Interleukin-17; Interleukins; Knock-out; Lead; Ligands; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Lymphoid Cell; Mediating; Membrane Glycoproteins; Mentors; Molecular Target; Morbidity - disease rate; Mus; Myeloid Cells; Network-based; Pathway interactions; Patients; Phenotype; Physicians; Play; Prevalence; Pulmonary Inflammation; Refractory; Regulation; Regulatory T-Lymphocyte; Research; Respiratory Failure; Respiratory physiology; Role; Scientist; Signal Transduction; Steroid Resistance; Steroids; T cell differentiation; T cell response; T-Lymphocyte; Testing; Th2 Cells; Training; Training Programs; Viral Tumor Antigens; Work; airway inflammation; career; cell type; cytokine; in vivo; inflammatory lung disease; insight; interleukin-23; mortality; new therapeutic target; novel; pleiotropism; podoplanin; public health relevance; receptor; response; transcriptome; transcriptomics; whole genome

 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.

 描述（由适用提供）：哮喘是气道高度普遍的炎症性疾病，可导致严重的支气管收缩和呼吸衰竭。约有10％的患者患有严重，持续，难以控制哮喘，尤其是白介素（IL）-17介导的，中性粒细胞性气道注射的患者，无论单独或与2型炎症。不幸的是，嗜中性哮喘的患者对当前疗法的反应较差，包括当前哮喘治疗，皮质类固醇的主要疗法，强调了鉴定能够同时调节2型和17型反应的分子靶标的重要性。 我们最近确定了Podoplanin（PDPN），这是一种表面糖蛋白，最好由Th17细胞表达，是效应CD4 T细胞反应的新型阴性调节剂。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）的小鼠是在树突细胞（DC）上表达的PDPN配体（DCS），它会出现赞助者气动炎症，该炎症标志着Th2和Th17细胞浸入了肺中的Th2和Th17细胞的增加。因此，假设PDPN+ T细胞与CLEC-2+树突状细胞之间的相互作用会导致两种细胞类型的双向调节，并且对于控制2型和17型介导的气道注射至关重要。我们建议通过鉴定肺居民CLEC-2+抗原呈现细胞类型来研究这一假设，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方法来识别由CLEC-2信号控制的关键免疫调节电路。此外，我们建议研究DC上CLEC-2表达通过影响效应的CD4 T细胞分化来调节2型和17型免疫复杂的机制，从而调节调节t的功能 细胞以及影响肺居民先天淋巴样细胞（ILC），特别是通过使用单细胞转录组方法来识别ILC功能的关键调节剂。 在我的心态的指导下，我已经制定了一项为期五年的培训计划，以提供成为一个独立的物理科学家所需的技术和教学培训，专注于研究肺部感染中的免疫调节途径。重要的是，该项目将由科学咨询委员会监督该项目，该委员会在研究肺部感染和Immunocells的转录组分析方面提供专业知识，这是该提案的两个关键领域。因此，该建议将提供培训和科学基础 为了实现我的最终目标，即成为控制免疫介导的肺部疾病的独立资助的身体科学家。