Metabolic Reprogramming in Laryngotracheal Stenosis

喉气管狭窄的代谢重编程

基本信息

批准号：
9590279
负责人：
Alexander Hillel
金额：
$ 16.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9590279
关键词：
Adjuvant Therapy Adult Adverse effects Amino Acids Aphonia Aspartate-Ammonia Ligase Automobile Driving Award Breathing Carbon Cell Proliferation Cells Cerebral Malaria Chronic Disease Cicatrix Clinical Collagen Communication Disability Deposition Development Disease Dysphonia Energy-Generating Resources Enzymes Faculty Fibroblasts Fibrosis Gene Expression Glioblastoma Glutamates Glutaminase Glutamine Glycolysis Head and Neck Surgery Health Care Costs Histology Human Iatrogenesis Immunohistochemistry In Vitro Individual Infant Intubation Laboratories Larynx Malignant Neoplasms Medical Metabolic Metabolism Mus Nitrogen Norleucine Normal tissue morphology Nucleic Acids Otolaryngology Oxidative Phosphorylation Pathologic Processes Patients Persons Pharmaceutical Preparations Phenotype Placebos Pre-Clinical Model Production Proliferating Purines Pyrimidine Regenerative Medicine Research Role Secondary to Stenosis Stents Subglottis structure Surface Surgical Management Techniques Testing Therapeutic Trachea Tracheostomy procedure Tube Validation Voice Warburg Effect Work aerobic glycolysis cancer cell cancer therapy career clinical practice gastrointestinal human tissue idiopathic pulmonary fibrosis improved in vivo inhibitor/antagonist materials science medical schools member mortality mouse model novel strategies novel therapeutics pre-clinical prevent protein expression translation to humans tumor metabolism

项目摘要

Summary 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 voice and airway disorders. With the support of an Early Career Research Award, Dr. Hillel seeks to better understand metabolic mechanisms of laryngotracheal stenosis (LTS) and apply regenerative medicine techniques to its treatment. Specifically, Dr. Hillel will be focusing on glutamine metabolism and targeted inhibition of glutamine as a novel approach to treating LTS in vitro on human LTS-scar fibroblasts and in vivo in a validate mouse model of LTS. As a part of this study, he plans to utilize a drug-eluting stent to target these metabolic mechanisms in a preclinical model. Aim 1 will be performed in mice to determine the ability of 6-diazo-5-oxo-l-norleucine (DON), a glutamine inhibitor, to prevent fibrosis. Systemic DON therapy will be compared with topical DON administration via a drug eluting stent. One of the enzymes DON blocks is glutaminase, which converts glutamine into glutamate. Aim 2 will specifically investigate glutaminase inhibition in human tracheal fibroblasts in vitro and in LTS mice in vivo. Preclinical validation of glutamine inhibition as a treatment for LTS is a critical step prior to translation to human studies.

概括 Alexander Hillel 博士是耳鼻喉头颈外科系的教员约翰·霍普金斯医学院，他的临床实践致力于内科和外科声音和气道疾病的管理。在早期职业研究奖的支持下，希勒尔博士寻求更好地了解喉气管狭窄（LTS）的代谢机制并应用再生医学技术对其治疗。具体而言，希勒尔博士将重点关注谷氨酰胺代谢和靶向抑制谷氨酰胺作为体外治疗人类 LTS 疤痕成纤维细胞的 LTS 的新方法体内 LTS 验证小鼠模型。作为这项研究的一部分，他计划利用药物洗脱支架在临床前模型中针对这些代谢机制。目标 1 将在小鼠中进行以确定 6-diazo-5-oxo-l-norleucine (DON)（一种谷氨酰胺抑制剂）预防纤维化的能力。全身 DON 治疗将与通过药物洗脱支架局部 DON 给药进行比较。 DON 阻断酶之一是谷氨酰胺酶，将谷氨酰胺转化为谷氨酸。目标 2 将专门研究谷氨酰胺酶抑制在体外人类气管成纤维细胞和体内 LTS 小鼠中。谷氨酰胺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。