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.

Alexander Hillel 博士是耳鼻喉头颈科的教员在约翰·霍普金斯大学医学院进行外科手术，他的临床实践致力于声门下狭窄的药物和手术治疗。通过R01的支持他和共同研究员 Ramana Sidhaye 博士寻求更好的研究项目资助了解功能失调的上皮屏障如何导致自发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，上呼吸道形成疤痕使声门下喉变窄，导致呼吸急促和交流困难残疾。具体来说，研究小组将重点关注 E-cadherin，一种 apico-adherens 上皮中的连接蛋白，是 iSGS 屏障功能障碍的原因。缺乏E- 钙粘蛋白创建一个可渗透的屏障，允许常见抗原通过上皮细胞并引发纤维化。该提案将研究上皮细胞中E-钙粘蛋白的丢失如何细胞在小鼠模型中导致疤痕形成，并通过使用人类上皮细胞和从 iSGS 患者生物样本中分离出的成纤维细胞。它还将研究一种新颖的外科手术切除疤痕组织后恢复上皮，以评估 E-钙粘蛋白是否是关键参与防止疤痕重新形成的蛋白质。最后，该提案将调查通过称为岩藻糖基化的过程改善糖与 E-钙粘蛋白的结合，作为一种新型恢复E-钙粘蛋白和上皮屏障功能的治疗。通过体外结合和体内建模、iSGS 患者的参与以及对新型手术的评估程序中，研究团队独特地准备改变我们的理解和 iSGS 治疗。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Murine Model of Airway Fibrosis has Anatomic, Physiologic, and Molecular Congruency to Human iSGS.

气道纤维化小鼠模型与人类 iSGS 具有解剖学、生理学和分子一致性。

DOI：
发表时间：
2024-01
期刊：
影响因子：
0
作者：
Mafla, Laura M;Ospino, Rafael;So, Raymond J;Berges, Alexandra J;Collins, Samuel L;Chan;Abd;Motz, Kevin;Hillel, Alexander T
通讯作者：
Hillel, Alexander T