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

E-钙粘蛋白在特发性声门下狭窄上皮屏障功能障碍和纤维化中的作用

基本信息

批准号：
10756248
负责人：
Alexander Hillel
金额：
$ 15.41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10756248
关键词：
Adherens Junction Adhesions Affect Antigens Binding Biological Models Biopsy Cell-Cell Adhesion Cells Cicatrix Coculture Techniques Communication Disability Dedications Defect Development Disease Dysphonia E-Cadherin Epithelial Cells Epithelium Etiology Excision Faculty Fibroblasts Fibrosis Fluorescence-Activated Cell Sorting Functional disorder Gene Expression Genes Head and Neck Surgery Histopathology Human Immune Immunofluorescence Immunologic In Vitro International Lamina Propria Larynx Life Longitudinal Studies Maps Medical Mucous Membrane Mus National Institute on Deafness and Other Communication Disorders Obstruction Operative Surgical Procedures Organ Transplantation Otolaryngology Pathologic Patient Participation Patients Perimenopause Permeability Phenotype Play Prevention Process Proteins Provider Recurrence Repeat Surgery Research Research Personnel Research Project Grants Role Sampling Shortness of Breath Specimen Stenosis Subglottis structure Surgical Management Testing Tissues Western Blotting Wild Type Mouse Woman airway epithelium clinical practice improved in vivo Model innovation knock-down lentivirally transduced medical schools member mouse model multidisciplinary novel novel therapeutics occludin overexpression prevent prospective protein expression restoration satisfaction single-cell RNA sequencing spatial relationship surgery outcome transcriptome sequencing transcriptomics

项目摘要

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.

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