Targeting mTOR regulation of T-lymphocytes and fibroblasts in Laryngotracheal Stenosis

喉气管狭窄中 T 淋巴细胞和成纤维细胞的靶向 mTOR 调节

基本信息

批准号：
10613459
负责人：
Alexander Hillel
金额：
$ 71.11万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613459
关键词：
Airway Disease Attenuated Autologous Biocompatible Materials Biological Models Breathing CD4 Positive T Lymphocytes Cell Communication Cells Chronic Disease Chronic Obstructive Pulmonary Disease Cicatrix Clinical Trials Coculture Techniques Collaborations Collagen Communication Disability Coronary Data Dedications Development Diabetes Mellitus Disease Dysphonia Engineering FDA approved FOXP3 gene FRAP1 gene Faculty Fibroblasts Fibrosis Flow Cytometry Funding Gene Expression Head and Neck Surgery Histopathology Homeostasis Human Iatrogenesis Immune In Vitro Individual Intubation Laboratories Laryngeal Diseases Larynx Mediating Medical Metabolic Metabolism Methods Mus National Institute on Deafness and Other Communication Disorders Otolaryngology Pathogenesis Pathologic Pathologic Processes Patient Participation Patients Persons Pharmaceutical Preparations Phenotype Pilot Projects Population Proliferating Regenerative Medicine Regulation Regulatory T-Lymphocyte Research Research Personnel Research Project Grants Role Scientist Sirolimus Site Sorting Specimen Stenosis Stents Surgical Management T cell differentiation T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Therapeutic Effect Trachea Tracheostomy procedure Tube Validation Work airway obstruction cell growth clinical practice cost cytokine design druggable target efficacy evaluation improved in vivo in vivo Model mTOR Inhibitor mTOR inhibition mTOR protein medical schools member mortality mouse model novel novel strategies novel therapeutics pre-clinical prevent restenosis side effect single cell mRNA sequencing single cell sequencing translation to humans wound healing

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 laryngotracheal stenosis. With the support of a R01 Research Project Grant, he seeks to better understand mechanisms of laryngotracheal stenosis (LTS) and apply regenerative medicine techniques to its treatment. Specifically, Dr. Hillel will be focusing on the mTOR mechanism and targeted inhibition of mTOR as a novel approach to treating LTS in vitro on human LTS-scar fibroblasts and in vivo in a validated mouse model of LTS. This proposal will study the mechanism of how mTOR suppression works on the pathologic T-cell and fibroblast subsets that are critical to the development of iLTS. It also will study how the dysregulated T-cell subsets interact with healthy and diseased fibroblasts to understand the pathogenesis of this devastating disease. Finally, the proposal will test a novel drug eluting stent to deliver mTOR suppression directly to the site of disease in the larynx and trachea to target diseased T-cells and fibroblasts without side effects of systemic mTOR inhibition. Through a combination of in vitro and in vivo modeling, participation from patients with iLTS, and a novel biomaterials approach, the investigator team is uniquely poised to transform our understanding and treatment of LTS. Preclinical validation of mTOR inhibition as a treatment for LTS is a critical step prior to translation to human studies.

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喉气管狭窄的药物和手术治疗。在R01的支持下研究项目资助，他寻求更好地了解喉气管狭窄的机制（LTS）并将再生医学技术应用于其治疗。具体而言，希勒尔博士将专注于 mTOR 机制和 mTOR 的靶向抑制作为一种新方法在体外对人类 LTS 疤痕成纤维细胞进行 LTS 处理，并在经过验证的小鼠模型中进行体内 LTS 处理 LTS。该提案将研究 mTOR 抑制如何作用于对 iLTS 发展至关重要的病理性 T 细胞和成纤维细胞亚群。它还将研究失调的 T 细胞亚群如何与健康和患病的成纤维细胞相互作用了解这种毁灭性疾病的发病机制。最后，该提案将测试一部小说药物洗脱支架可将 mTOR 抑制直接传递至喉部疾病部位，气管靶向患病 T 细胞和成纤维细胞，且没有全身 mTOR 的副作用抑制。通过体外和体内建模相结合，患者的参与 iLTS 和一种新颖的生物材料方法，研究团队独特地准备转变我们对 LTS 的理解和治疗。 mTOR 抑制作用的临床前验证 LTS 的治疗是转化为人体研究之前的关键一步。