E-cadherin deficient epithelium drives airway fibrosis in idiopathic subglottic stenosis

Project Summary Dr. Alexander Hillel is a faculty member in the Department of Otolaryngology-Head & Neck Surgery at the Johns Hopkins School of Medicine where his clinical practice is dedicated to the medical and surgical management of subglottic stenosis. Through the support of a R01 Research Project Grant, he and co-Investigator, Dr. Ramana Sidhaye, seek to better understand how the dysfunctional epithelial barrier contributes to the spontaneous fibrosis seen in idiopathic subglottic stenosis (iSGS). iSGS is a rare but life-threatening disease that exclusively affects healthy, peri-menopausal women. In iSGS, scar forms in the upper airways narrowing the subglottic larynx, and resulting in shortness of breath and communication disability. Specifically, the investigator team will focus on E-cadherin, an apico-adherens junction protein in epithelium, as the cause for barrier dysfunction in iSGS. The deficiency in E- cadherin creates a permeable barrier allowing for common antigens to pass through the epithelium and trigger fibrosis. This proposal will study how the loss of E-cadherin in epithelial cells leads to scar formation in a mouse model and by using human epithelial cells and fibroblasts isolated from iSGS patient biospecimens. It will also study a novel surgical procedure that restores the epithelium after excising scar tissue to assess if E-cadherin is the critical protein involved in preventing scar from reforming. Finally, the proposal will investigate improving saccharide binding to E-cadherin, through a process called fucosylation, as a novel therapy to restore E-cadherin and epithelial barrier function. Through a combination of in vitro and in vivo modeling, participation from patients with iSGS, and assessment of a novel surgical procedure, the investigator team is uniquely poised to transform our understanding and treatment of iSGS.