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

• 批准号: 10384685
• 负责人: Alexander Hillel
• 金额: $ 8.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10384685
• 关键词: Biocompatible Materials; Breathing; Cicatrix; Communication Disability; Development; Disease; FRAP1 gene; Faculty; Fibroblasts; Head and Neck Surgery; Human; In Vitro; Larynx; Medical; Otolaryngology; Pathogenesis; Pathologic; Patient Participation; Patients; Regenerative Medicine; Regulation; Research Personnel; Research Project Grants; Site; Stenosis; Stents; Surgical Management; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Trachea; Tube; Validation; Work; airway obstruction; clinical practice; in vivo; in vivo Model; mTOR inhibition; medical schools; member; mortality; mouse model; novel; novel strategies; novel therapeutics; pre-clinical; side effect; translation to humans

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.

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 喉气管狭窄的内科和外科治疗。在R 01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治疗。具体来说，希勒尔博士将 关注mTOR机制和靶向抑制mTOR作为一种新的方法， 在体外对人LTS-瘢痕成纤维细胞和在体内在经验证的小鼠模型中治疗LTS， LTS.该提案将研究mTOR抑制如何在细胞中起作用的机制。 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，提案将测试一部小说 药物洗脱支架将mTOR抑制直接递送至喉部疾病部位， 气管靶向病变T细胞和成纤维细胞，而没有全身性mTOR的副作用 抑制作用通过体外和体内建模的组合， iLTS和一种新的生物材料方法，研究人员团队独特地准备将其转化为 我们对LTS的理解和治疗。临床前验证mTOR抑制作为 LTS的治疗是转化为人类研究之前的关键步骤。