Lung function is essential to sustain life and depends on the continuous neutralization of inhaled pathogens, particles, and noxious substances. The mucosal epithelial barrier of the lung is the first line of defense against contaminants. In the case of a compromised mucosal epithelial barrier, epithelial alarmins recruit inflammatory responses to neutralize threats and aid in the restoration of lung homeostasis. The mechanisms that regulate inflammation must accommodate sensitivity to pathogens while preventing excessive inflammation that results in further epithelial damage. That excessive inflammation is a defining feature of major lung diseases like asthma and COPD underscores the need for regulatory mechanisms that safeguard the lung against excessive inflammation. The interaction between receptor C-type lectin-like 2 (Clec-2) and its ligand Podoplanin (Pdpn) has been found to regulate inflammatory responses in various tissues. We found that both Clec-2-deficiency and Pdpn- deficiency cause spontaneous lung inflammation and asthma-like disease in mice. Specific blocking of Clec- 2/Pdpn interaction increases the epithelial production of alarmins and the susceptibility to allergic asthma. Taken together, we hypothesize that Clec-2/Pdpn crosstalk is a mechanism that, when intact, resists inflammation and promotes lung homeostasis. We propose to exploit single-cell genomics to identify all of the cell types and subsets that express Clec-2 and Pdpn, and to spatially map them over the lung's anatomy. In so doing, we will identify putative cellular circuits that mediate Clec-2/Pdpn interactions, and test these circuits using in vivo mouse genetics. Finally, we propose to investigate the cellular mechanisms that link Clec-2/Pdpn crosstalk to the regulation of epithelial alarmins and lung inflammation. Overall, we will use Clec-2/Pdpn interactions as an entry point to exploring the cellular circuits and molecular mechanisms that safeguard lung homeostasis, with the goal to identify new therapeutic targets for inflammatory diseases. My ultimate training goal is to become an independent scientist focusing on cellular circuits that support lung function and that are dysregulated in disease. With the guidance and mentorship of Dr. Aviv Regev at the Broad Institute and Dr. Vijay Kuchroo at Brigham and Women's Hospital, I composed a training plan that will provide me the essential technical and pedagogical training to successfully advance my training goals.
Excessive inflammation is a hallmark of major lung diseases including asthma and COPD. Clec-2/Pdpn interactions inhibit lung inflammation by an unknown mechanism, and their loss increases asthma severity. We propose to investigate Clec-2/Pdpn interactions in order to identify the cellular circuits and molecular mechanisms that mediate their protective effects, with the ultimate goal of illuminating novel biological pathways and therapeutic targets for inflammatory diseases.
