Thursday, September 19, 2024
9/19/2024
PROJECT SUMMARY Asthma is characterized by chronic, non-resolving lung inflammation; however, there are endogenous inhibitory mechanisms that normally promote the resolution of lung inflammation. The long-term objective of our research is to understand the bronchial epithelial cell (BEC)-mediated inhibition of lung inflammation in asthma. Transmembrane protein 178 (Tmem178) mediates a novel endogenous inhibitory mechanism in asthma. Our preliminary data showed that TMEM178 gene expression in BECs decreased as asthma severity increased. In addition, we found that Tmem178 inhibits adenosine triphosphate- and allergen-induced [Ca2+]i responses, store- operated calcium entry (SOCE), and interleukin (IL)-33 release in BECs. Furthermore, the genetic loss of Tmem178 led to more severe lung inflammation, airway hyperresponsiveness, and airway collagen deposition in a murine model of asthma. Finally, we identified TMEM178 variants associated with severe clinical phenotypes in asthma patients. Based on our preliminary data, we hypothesize that the Tmem178-mediated endogenous inhibitory mechanism in BECs is dysregulated in asthma, resulting in downstream lung inflammation, AHR, and tissue remodeling. In this project, we will test this hypothesis by complementary approaches using BEC cultures and mouse models of asthma together with whole-genome sequencing, RNA sequencing, and clinical data from diverse asthma cohorts. In Aim 1, we will test the hypothesis that Tmem178-mediated inhibition of calcium responses is disrupted in asthmatic BECs. We will analyze calcium imaging from normal and asthmatic BECs and organotypic cultures of normal and asthmatic BECs. In Aim 2, we will test the hypothesis that the targeted genetic loss of Tmem178 in epithelial cells results in more severe lung inflammation, airway hyperresponsiveness, and airway collagen deposition. We will analyze Tmem178fl/flShhCre mice in a murine model of asthma. In Aim 3, we will test the hypothesis that TMEM178 variants are associated with TMEM178 expression and [Ca2+]i responses in BECs and severe asthma phenotypes in patients. We will analyze existing whole-genome sequencing, RNA sequencing, and clinical data from diverse asthma cohorts, and use CRISPR/Cas9 editing to generate and study TMEM178 variants in BECs. The results of our proposed research will characterize the role of Tmem178 in BECs and asthma pathogenesis, thereby providing a rationale for the development of novel therapies to resolve inflammation in the asthmatic lung.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
