Nasal Airway Epithelia Expression Genetics and Epigenetics in Puerto Rican Asthmatics. In collaboration with Dr. Jose Rodriguez Santana (Pneumologia Pediatria, Puerto Rico) and Dr. Esteban Burchard (University of California, San Francisco) we are analyzing the expression genetics and epigenetics of nasal airway epithelial cells from Puerto Rican asthmatics. Recent work clustering asthmatics based on their clinical characteristics, gene expression, and immune cell levels has indicated that asthma is a heterogeneous spectrum of related disorders rather than a single disease with a single etiological basis. Determination of the molecular signature for these different subgroups will aide greatly in the mechanistic understanding of these different subgroups and the development of new, targeted asthma therapies. The nasal epithelium is an ideal tissue to study as it is easily accessible and is closely related both structurally and functionally to the bronchial epithelium, which plays a key role in asthma development. As such this work may yield a clinically accessible asthma biomarker.
Functional characterization of an IPF genetic risk variant. Although genetic predisposition is presumed to be involved in the etiology of idiopathic pulmonary fibrosis (IPF) few specific risk variants have been identified. Using a multi-stage genetic screen working with Dr. David Schwartz, Dr. Greg Cosgrove, and Dr. Tasha Fingerlin we have identified a genetic risk factor for IPF carried by 67% of IPF patients. This genetic variant is in the promoter region of the MUC5B gene and based on preliminary analyses is expected to alter expression of the MUC5B gene. Using allele-specific analyses we are exploring how this genetic variant alters the recruitment of transcriptional machinery to the MUC5B promoter and thus expression of the MUC5B gene in the IPF lung. These studies will provide mechanistic insight into how the MUC5B promoter variant increases risk of IPF disease development.
Genomic editing of primary lung cells. Although GWAS studies for complex lung diseases have resulted in the identification of a large number of genetic risk variants it has proved more difficult to discern how risk variants and genes fit into disease pathology. A major step towards discerning how genetic variants contribute to asthma development is determination of the molecular function of the risk variant in lung cells relevant to disease. We are using genome-editing methods to study the expression and functional effects of genetic disease variants in primary lung cells. Understanding molecular variant effects will foster detailed mechanistic studies, which will increase understanding of disease biology and identify new targets for therapy.
Genetics of expression in asthmatic bronchial epithelium. Recent work has shown that the bronchial epithelium plays a key role in the development of asthma, functioning as a barrier, interacting with immune cells, and producing mucus that frequently obstructs the airways of asthmatics. Our collaborator Dr. John Fahy (University of California-San Francisco) has shown that the expression pattern of the bronchial epithelium is dysregulated in asthma. We are working with Dr. Fahy to determine the genetic variants that control the dysregulated expression of genes in the bronchial epithelium of asthmatics. This work will aide in the identification of genetic biomarkers in asthma.