Immune Cell Modulation in Laryngotrachael Fibrosis

 描述（由申请人提供）：亚历山大希勒尔博士是约翰霍普金斯医学院耳鼻咽喉头颈外科系的初级教员，他的临床实践致力于嗓音和气道疾病的医疗和手术管理。在导师职业发展奖的支持下，Hillel博士寻求更好地了解喉气管纤维化（LTF）的炎症机制，并将再生医学技术应用于其治疗。具体而言，Hillel博士将专注于雷帕霉素（mTOR）的哺乳动物靶点，该靶点已被证明可以激活与LTF早期模型中观察到的肺纤维化中相同类型的T细胞和巨噬细胞。最终，他计划开发一种药物洗脱支架来靶向免疫机制。目的1将表征小鼠气管中机械损伤的炎症反应，然后在一种新的体内原位小鼠模型中确定mTOR在调节LTF之前的巨噬细胞和T淋巴细胞中的作用。目的2将描述巨噬细胞、T淋巴细胞及其炎性细胞因子在LTF患者和有发生LTF风险的患者中的作用。最后，目标2将重点确定一种理想的生物可吸收聚合物，以设计早期目标中确定的药物洗脱气道支架靶向机制。Hillel将通过免疫学，生物统计学和伦理研究课程提高他的研究知识和技能，接受经验丰富的研究人员跨学科团队的指导指导，并沉浸在约翰霍普金斯医学院，约翰霍普金斯彭博公共卫生学院，以及位于威斯康星州麦迪逊的威斯康星州医学研究所的喉部研究小组。这个职业发展奖将为Hillel博士提供他成为语音科学研究的独立研究者和未来领导者所需的资源。

 DESCRIPTION (provided by applicant): Dr. Alexander Hillel is a junior 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 a Mentored Career Development Award, Dr. Hillel seeks to better understand the inflammatory mechanisms of laryngotracheal fibrosis (LTF) and apply regenerative medicine techniques to its treatment. Specifically, Dr. Hillel will be focusing on mammalian target of rapamycin (mTOR), which has been shown to activate the same type of T cells and macrophages in pulmonary fibrosis that has been observed in early models of LTF. Ultimately, he plans to develop a drug-eluting stent to target the immune mechanisms. Aim 1 will characterize the inflammatory response to mechanical injury in the mouse trachea and then determine the role of mTOR in regulating macrophages and T-lymphocytes that precede LTF in a novel in vivo in situ mouse model. Aim 2 will characterize the role of macrophages, T-lymphocytes, and their inflammatory cytokines in patient with and patients at risk for developing LTF. Finally, Aim 2 will focus on identifying an ideal bioabsorbable polymer to engineer a drug-eluting airway stent targeting mechanisms identified in earlier aims. During the course of this proposal, Dr. Hillel will enhance his research knowledge and skills with coursework in immunology, biostatistics, and ethical research, receive directed mentorship by an interdisciplinary team of experienced researchers, and be immersed in the interdisciplinary research and clinical environments of the Johns Hopkins School of Medicine, Johns Hopkins Bloomberg School of Public Health, and the Laryngeal Research Group at The Wisconsin Institute of Medical Research in Madison, Wisconsin. This Career Development Award will provide Dr. Hillel with the resources that he needs to become an independent investigator and future leader in voice science research.