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.
Laryngotracheal stenosis (obstructing scar in the larynx and trachea) occurs in patients after long-term breathing tube placement and can result in communication disability and high mortality rates due to the obstructed airway. The critical barrier to improving treatment for laryngotracheal stenosis is the limited understanding of the mechanisms behind the development of scar in the airway. This proposal will investigate inhibition of glutamine to alter metabolism within scar fibroblasts and apply a materials science strategy for topical therapy in the larynx and trachea.
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