Metabolic Reprogramming in Laryngotracheal Stenosis

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。

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.