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.
Asthma is a highly prevalent inflammatory disorder of the airways that can lead to severe bronchoconstriction and death. We propose to investigate the role of a novel immunoregulatory pathway (CLEC-2/Pdpn) in regulating airway inflammation, with an ultimate goal of identifying novel therapeutic targets and providing insight into the pathobiology of severe asthma.
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