Mechanism Guided Therapy for Laryngopharyngeal Reflux

项目总结/摘要 咽喉反流（LPR）的一般方法，这是一种流行的异质性综合征， 其喉部症状归因于胃食管反流，导致不良的健康结果， 不适当的资源利用和巨大的医疗成本。作为一名拥有先进技术的医生科学家 在食管生理学和健康结果研究的培训，我的长期职业目标是发现 针对食管疾病的表型引导护理范例，如LPR，侧重于不同的疾病 机制我从单组临床试验、观察性研究和初步研究中获得的初步发现， LPR的转化研究产生了一个中心假设，即新的诊断生物标志物可以 鉴定LPR的临床生理表型并指导机制聚焦治疗策略。因此 本提案的研究目标是：（1）测量新型治疗性上食管 括约肌辅助装置在一项严格的生物标志物靶向随机化假对照试验中的78例受试者， 唾液胃蛋白酶阳性LPR，（2）采用综合潜伏类分析法鉴定LPR表型 生理和临床数据，以及（3）比较具有和不具有胃蛋白酶的受试者之间的口腔微生物组 正LPR。研究目标与我的培训目标相一致，即（1）发展先进的专业知识 临床试验方法，（2）获得表型设计和潜在类别分析的技能，（3）获得经验 转译微生物组研究。我的优秀和多样化的导师团队是由小学监督 导师Samir Gupta博士是一位临床试验专家，为结直肠癌的开创性发现做出了贡献 筛选共同导师包括约翰·潘多尔菲诺博士，一位领先的国际权威和临床研究人员， 食管生理学，以及Bernd Schnabl博士，他是一位内科科学家，在宿主对 肠道微生物组在大学的特殊支持和有利的制度环境 加州大学圣地亚哥分校（UCSD）是该应用程序的关键优势。UCSD的NIH支持的临床 转化研究所将提供尖端的临床试验基础设施。UCSD中心 食管疾病和声音与吞咽疾病中心将确保成功招募受试者 以及最先进的诊断技术UCSD的P30支持消化系统疾病研究 中心由Bernd Schnabl博士指导，将提供微生物和生物信息学方面的领先资源。 该提案的直接预期影响是为LPR的临床管理提供信息， 关于LPR中炎症的新机制途径，以及通过提供独特的 临床试验方法和微生物组研究技能。最终，这份职业发展提案将 开始我的职业生涯作为一个有影响力的领导者在多学科的临床转化研究领域的航空航天， 消化道食管疾病

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.