Mechanisms of adverse gastrointestinal events during oral immunotherapy

摘要 此K23奖申请要求对助理Benjamin Wright博士的职业发展提供支持 亚利桑那州马约诊所过敏、哮喘和临床免疫学部教授。候选人的 总体目标是成为一个独立的，临床研究者和改善个人的健康与 嗜酸性粒细胞性食管炎（EoE）和食物过敏通过以病人为导向的研究。该奖项将提供 为实现这一目标所需的培训和支持。具体来说，这项提议将使赖特博士能够 完成以下短期职业目标：（1）获得临床研究方法和设计方面的培训 （2）培养基础/转化研究技术的技能;（3）培养专业人员; 领导翻译研究团队所需的技能;（4）收集初步数据和生物标本， 随后R 01申请并建立了食物过敏和嗜酸性粒细胞 胃肠道疾病口服免疫疗法（OIT）是一种新兴的食物过敏治疗方法。虽然大多数 患者可以成功地用OIT脱敏，许多人产生胃肠道副作用，包括EoE。 EoE是一种与严重食管功能障碍相关的慢性过敏性疾病。的具体目标 研究计划是检查OIT胃肠道副作用的潜在机制， 开发一种新的治疗策略来预防它们。为了实现这一点，我们将执行一个子研究， 在接受牛奶OIT（含或不含dupilumab）治疗的牛奶过敏患者中进行的安慰剂对照试验。期间 在这项试验中，我们将连续监测嗜酸性粒细胞炎症、食管屏障功能障碍的标志物和免疫功能。 外周血和食管中的反应。为了支持赖特博士的职业发展，他将 获得细胞免疫学的技能，并完成基础科学实习，重点是尖端 临床样品的蛋白质组学分析。此外，他还将完成正式的临床教学课程， 研究设计、生物统计学和生物伦理学。赖特博士召集了一个指导委员会 由食物过敏、EoE、蛋白质组学、嗜酸性粒细胞生物学和2型免疫方面的国际专家组成 唯一适合解决本提案中提出的假设，并指导赖特博士的职业生涯 发展该提案结合了马约诊所的研究环境和正在进行的 与斯坦福大学合作，为进行上述培训和 研究目标。在本计划结束时，赖特博士将具备所需的技能和经验， 过渡到独立，并领导一个翻译研究团队。该项目的成功完成将 通过提供关键的食物过敏治疗， 深入了解食物过敏和EoE的发病机制。

ABSTRACT This K23 award application requests support for the career development of Dr. Benjamin Wright, Assistant Professor in the Division of Allergy, Asthma and Clinical Immunology at Mayo Clinic Arizona. The candidate’s overall goal is to become an independent, clinician-investigator and improve the health of individuals with eosinophilic esophagitis (EoE) and food allergy through patient-oriented research. This award will provide the training and support needed to accomplish this goal. Specifically, this proposal will enable Dr. Wright to accomplish the following short-term career goals: (1) acquire training in methods and design of clinical studies and trials in food allergy; (2) develop skills in basic/translational research techniques; (3) develop professional skills necessary to lead a translational research team; and (4) gather preliminary data and biospecimens for a subsequent R01 application and establish an independent research program in food allergy and eosinophilic gastrointestinal disorders. Oral immunotherapy (OIT) is an emerging treatment for food allergy. Although most patients can be successfully desensitized with OIT, many develop gastrointestinal side effects including EoE. EoE is a chronic allergic condition associated with severe esophageal dysfunction. The specific goals of the research proposal are to examine the mechanisms underlying the gastrointestinal side effects of OIT and to develop a novel treatment strategy to prevent them. To accomplish this, we will perform a sub-study of a placebo-controlled trial in patients with milk allergy treated with milk OIT with or without dupilumab. During the trial, we will serially monitor eosinophilic inflammation, markers of esophageal barrier dysfunction, and immune responses in peripheral blood and in the esophagus. To support Dr. Wright’s career development, he will acquire skills in cellular immunology and complete a basic science internship focusing on cutting-edge proteomic analysis of clinical samples. In addition, he will complete formal didactic coursework in clinical research study design, biostatistics, and bioethics. Dr. Wright has assembled a mentoring committee comprised of international experts in food allergy, EoE, proteomics, eosinophil biology, and type 2 immunity uniquely suited to address the hypotheses set forth in this proposal and guide Dr. Wright’s career development. This proposal combines the strength of the research environment at Mayo Clinic and an ongoing collaboration with Stanford University that provides an ideal setting to pursue the aforementioned training and research goals. At the conclusion of this program, Dr. Wright will have the skillset and experience required to transition to independence and lead a translational research team. Successful completion of this project will likely provide a major and sustained impact on the care of patients with food allergy by providing critical insights into the pathogenesis of food allergy and EoE.