Role of E-cadherin in epithelial barrier dysfunction and fibrosis in idiopathic subglottic stenosis

亚历山大希勒尔博士是耳鼻咽喉头颈部的教员 约翰霍普金斯医学院的外科医生，他的临床实践致力于 声门下狭窄的内科和外科治疗。通过R 01的支持 研究项目赠款，他和共同研究员，博士拉马纳Sidhaye，寻求更好地 了解功能失调的上皮屏障如何导致自发性纤维化， 特发性声门下狭窄（iSGS）。iSGS是一种罕见但危及生命的疾病， 仅影响健康的围绝经期妇女。在iSGS中，瘢痕形成于上呼吸道 声门下喉变窄，导致呼吸和交流急促 残疾。具体来说，研究小组将重点关注E-钙粘蛋白，一种根尖粘附蛋白， 上皮中的连接蛋白，作为iSGS中屏障功能障碍的原因。缺乏E- 钙粘蛋白形成一个可渗透的屏障，允许常见的抗原通过 上皮并引发纤维化。本研究将探讨上皮细胞中E-钙粘蛋白的缺失是如何影响上皮细胞中E-钙粘蛋白的表达的。 细胞导致小鼠模型中的瘢痕形成，并通过使用人上皮细胞和 从iSGS患者生物样本中分离的成纤维细胞。它还将研究一种新的外科手术 在切除疤痕组织后恢复上皮，以评估E-钙粘蛋白是否是关键的 一种阻止疤痕形成的蛋白质。最后，提案将调查 通过一种称为岩藻糖基化的过程，改善糖与E-钙粘蛋白的结合，作为一种新的 治疗恢复E-钙粘蛋白和上皮屏障功能。通过结合体外 和体内建模，iSGS患者的参与，以及对一种新的手术方法的评估。 程序，调查员团队是独一无二的，以改变我们的理解和 iSGS治疗

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.