Mechanism Guided Therapy for Laryngopharyngeal Reflux

项目摘要/摘要 喉咽反流(LPR)是一种常见的异质性综合征 哪些喉部症状可归因于胃食道反流，导致健康状况不佳， 不适当的资源利用，以及巨大的医疗成本。作为一名先进的内科科学家 在食道生理和健康结果研究方面的培训，我的长期职业目标是发现 针对食道疾病的表型引导护理范例，如LPR，侧重于不同的疾病 机制。我在单臂临床试验、观察性研究和初步研究中的初步发现 LPR的翻译研究产生了一个中心假设，即新的诊断生物标记物可以 确定LPR的临床生理表型，并指导机制集中的治疗策略。因此， 这项建议的研究目标是：(1)评估新型食道上段治疗性治疗的疗效 括约肌辅助装置在一项严格的生物标志物定向随机假对照试验中的应用 唾液胃蛋白酶阳性LPR，(2)用潜伏类综合分析鉴定LPR表型 生理和临床数据，以及(3)有无胃蛋白酶受试者口腔微生物组的比较 LPR阳性。研究目标与我的培训目标是一致的：(1)发展高级专业知识 临床试验方法，(2)获得表型设计和潜伏期分析的技能，(3)获得经验 翻译微生物组研究。我的优秀和多样化的导师团队由小学 导师Samir Gupta博士，一位临床试验专家，在结直肠癌方面做出了开创性的发现 放映。共同导师包括约翰·潘多尔菲诺博士，他是一位领先的国际权威人士和 以及贝恩德·施纳布尔博士，他是一位内科科学家，在宿主对食道的影响方面开创了先河 肠道微生物群。大学特别支持和有利的制度环境 加州大学圣地亚哥分校(UCSD)是这一应用程序的关键优势。加州大学圣迭戈分校国立卫生研究院支持临床 翻译研究所将提供尖端的临床试验基础设施。加州大学圣地亚哥分校的 食道疾病和发声吞咽障碍中心将确保成功招募受试者 以及使用最先进的诊断技术。UCSD的P30支持的消化系统疾病研究 该中心由Bernd Schnabl博士领导，将提供微生物学和生物信息学方面的领先资源。 这项提议的直接预期影响是告知LPR的临床管理并阐明 关于LPR中炎症的新机制途径，以及通过提供独特的 掌握临床试验方法和微生物组研究的技能。最终，这项职业发展提案将 开始我的职业生涯，成为航空领域多学科临床-翻译研究的有影响力的领导者 消化性食道疾病。

PROJECT SUMMARY/ABSTRACT Generalized approaches for laryngopharyngeal reflux (LPR), a prevalent and heterogeneous syndrome in which laryngeal symptoms are attributed to gastroesophageal reflux, have led to poor health outcomes, inappropriate resource utilization, and tremendous healthcare costs. As a physician scientist with advanced training in esophageal physiology and health outcomes research, my long-term career goal is to discover phenotype guided care paradigms for esophageal conditions, such as LPR, focused on distinct disease mechanism. My preliminary findings from single-arm clinical trials, observational studies, and initial translational research in LPR have generated the central hypothesis that novel diagnostic biomarkers can identify clinical-physiologic phenotypes of LPR and guide a mechanism focused treatment strategy. Thus, the research goals of this proposal are to (1) measure the efficacy of the novel therapeutic upper esophageal sphincter assist device in a rigorous biomarker targeted randomized sham-controlled trial of 78 subjects with salivary pepsin positive LPR, (2) identify phenotypes of LPR using latent class analysis of comprehensive physiologic and clinical data, and (3) compare oral microbiome between subjects with and without pepsin positive LPR. The research aims are aligned with my training goals to (1) develop expertise in advanced clinical trial methods, (2) acquire skills in phenotype design and latent class analysis, and (3) obtain experience with translational microbiome research. My outstanding and diverse mentorship team is overseen by primary mentor Dr. Samir Gupta, an expert clinical trialist that has contributed seminal discoveries in colorectal cancer screening. Co-mentors include Dr. John Pandolfino, a leading international authority and clinical researcher in esophageal physiology, and Dr. Bernd Schnabl, a physician scientist that has pioneered work in host effects on the intestinal microbiome. The exceptionally supportive and conducive institutional environment at University of California San Diego (UCSD) is a key strength of this application. UCSD’s NIH supported Clinical Translational Research Institute will provide cutting-edge clinical trial infrastructure. UCSD’s Center for Esophageal Diseases and Center for Voice & Swallowing Disorders will ensure successful subject recruitment and access to state-of-the-art diagnostic techniques. UCSD’s P30 supported Digestive Diseases Research Center directed by Dr. Bernd Schnabl, will provide leading resources in microbiomics and bioinformatics. Immediate anticipated impacts of this proposal are to inform the clinical management of LPR and shed light on a novel mechanistic pathway of inflammation in LPR, as well as enhance my career by providing unique skills in clinical trial methods and microbiome research. Ultimately, this career development proposal will launch my career as an impactful leader in multi-disciplinary clinical-translational research in the field of aero- digestive esophageal diseases.