Metabolic Reprogramming in Laryngotracheal Stenosis

摘要 亚历山大·希勒尔博士是华盛顿大学耳鼻咽喉头颈外科的教员。 约翰霍普金斯医学院，在那里他的临床实践致力于内外科 嗓音和呼吸道疾病的管理。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 以医学技术对其进行治疗。具体地说，希勒尔博士将专注于谷氨酰胺代谢和 体外靶向抑制谷氨酰胺对人结缔组织瘢痕成纤维细胞的作用 在LTS验证的小鼠模型中进行体内实验。作为这项研究的一部分，他计划使用药物洗脱支架来 在临床前模型中针对这些代谢机制。目标1将在小鼠身上进行，以确定 谷氨酰胺抑制剂6-重氮-5-氧代-L去甲亮氨酸(DON)预防纤维化的能力。全身DON疗法 将通过药物洗脱支架与外用DON进行比较。唐布洛克身上的一种酶是 谷氨酰胺酶，将谷氨酰胺转化为谷氨酸。AIM 2将专门研究谷氨酰胺酶抑制 体外培养的人气管成纤维细胞和体内培养的小鼠气管成纤维细胞。谷氨酰胺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。

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.