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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.

总结博士亚历山大希勒尔是一个教员在耳鼻咽喉头颈外科在约翰霍普金斯医学院，他的临床实践致力于医疗和外科语音和气道疾病的管理。在早期职业研究奖的支持下，希勒尔博士旨在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来治疗。具体来说，希勒尔博士将专注于谷氨酰胺代谢，谷氨酰胺的靶向抑制作为一种新的方法来治疗LTS在体外对人LTS-瘢痕成纤维细胞和在LTS经验证的小鼠模型中体内。作为这项研究的一部分，他计划利用药物洗脱支架，在临床前模型中靶向这些代谢机制。目的1将在小鼠中进行，以确定 6-重氮-5-氧代-1-正亮氨酸（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的局部DON给药进行比较。DON阻断的一种酶是谷氨酰胺酶，将谷氨酰胺转化为谷氨酸。Aim 2将专门研究转氨酶抑制在体外人气管成纤维细胞中和在体内LTS小鼠中。谷氨酰胺抑制作为一种抗肿瘤药物的临床前验证 LTS的治疗是转化为人类研究之前的关键步骤。