喉气管狭窄中 T 淋巴细胞和成纤维细胞的靶向 mTOR 调节-猫眼课题宝

喉气管狭窄中 T 淋巴细胞和成纤维细胞的靶向 mTOR 调节

批准号：

10397577

负责人：

Alexander Hillel

金额：

$72.19万

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

项目状态：

未结题

起止时间：

2020-05-01 至 2025-04-30

来源：

https://reporter.nih.gov/project-details/10397577

关键词：

Airway Disease Attenuated Autologous Biocompatible Materials Biological Models Breathing CD4 Positive T Lymphocytes Cells Chronic Disease Chronic Obstructive Pulmonary Disease Cicatrix Clinical Trials Collaborations Collagen Communication Disability Coronary Data 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 Regenerative Medicine Regulation Regulatory T-Lymphocyte Research Research Personnel Research Project Grants Role Scientist Sirolimus Site Sorting - Cell Movement 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 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

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中文摘要

翻译

亚历山大·希勒博士是耳鼻咽喉头颈科的一名教员。在约翰霍普金斯医学院的外科手术，在那里他的临床实践致力于喉气管狭窄的内外科治疗。在R01的支持下格兰特研究项目，他试图更好地了解喉气管狭窄的机制 (LTS)，并应用再生医学技术进行治疗。具体地说，希勒博士将成为重点研究mTOR机制和靶向抑制mTOR作为一种新的治疗方法 LTS对人LTS-SCAR成纤维细胞的体外治疗作用和体内对LTS-SCAR小鼠模型的治疗这就是。这项建议将研究mTOR抑制如何在病理性T细胞和成纤维细胞亚群对iLTS的发展至关重要。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，该提案将检验一部小说药物洗脱支架将mTOR抑制直接输送到喉部和气管靶向病变T细胞和成纤维细胞，无全身mTOR副作用抑制力。通过体外和体内建模的结合，来自患者的参与 ILTS和一种新的生物材料方法，研究团队正准备独特地转变我们对LTS的理解和对待。MTOR抑制作为一种临床前验证在转化为人体研究之前，治疗LTS是关键的一步。

英文摘要

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.

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