The focus of this proposal is on GSDMB (gasdermin B) a gene on chromosome 17q21, a chromosomal region which has been highly linked to human asthma in several genome wide association studies. Moreover, as asthmatics with a SNP linked to chromosome 17q21 have increased expression of GSDMB, we generated transgenic mice which overexpress the human GSDMB transgene. Preliminary characterization of these GSDMB transgenic mice demonstrate that they have increased expression of the same GSDMB regulated pro-inflammatory and remodeling pathways we noted in human bronchial epithelial cells overexpressing GSDMB in vitro. The investigation of the function of GSDMB in the lung in asthma in this grant proposal will be facilitated by the development of unique reagents in the PI?s lab that are not commercially available (e.g. human GSDMB cre activated transgenic mice for cell specific conditional over- expression of the transgene; full length GFP labeled and unlabeled human GSDMB construct for in vitro studies; adenoviral human GSDMB construct to transfect into human lung bronchial epithelial cells in vitro). We will also study how GSDMB expressed in human lung ex vivo influences bronchodilation, bronchoconstriction, and airway remodeling using novel assays developed by my co-investigator Dr Kurten. The use of these novel approaches to study the function of GSDMB in human lung, as well as the development of novel reagents and GSDMB mutant mice will allow us to test the hypothesis that in vivo GSDMB expression in lung contributes to inflammation, and remodeling, with resultant effects on airway responsiveness. PAS-15-055: High Priority Immunology Grants (R01). This grant is submitted in response to PAS-15- 055 which requests research proposals that addresses innate and adaptive imm unity at the molecular, cellular, organism, and systems level (which we do in this study of GSDMB). In addition, proposals are requested that use innovative animal models (we have generated a novel conditional GSDMB transgenic mouse), and studies of the human immune system (we study human lung from severe asthmatics) with relevance to two topics of importance listed, i.e. human mucosal immunology and regulatory mechanisms in healthy vs severe asthmatic airways.
Although the gene GSDMB is highly associated with the development of asthma, little is known about the function of GSDMB and how it may contribute to the development of asthma. In this study we will use lung cells from humans as well as a mouse model of asthma to determine how GSDMB causes asthma. This may provide insight into novel treatments for asthma.
