Mechanisms of adverse gastrointestinal events during oral immunotherapy

摘要 此 K23 奖项申请请求支持助理 Benjamin Wright 博士的职业发展 亚利桑那州梅奥诊所过敏、哮喘和临床免疫学部门教授。候选人的 总体目标是成为一名独立的临床研究人员并改善患有以下疾病的个人的健康 通过以患者为导向的研究来研究嗜酸性粒细胞性食管炎（EoE）和食物过敏。该奖项将提供 实现这一目标所需的培训和支持。具体来说，该提案将使赖特博士能够 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 以及食物过敏试验； (2) 培养基础/转化研究技术的技能； （三）培养专业人才 领导转化研究团队所需的技能； (4) 收集初步数据和生物样本 随后R01的应用并建立食物过敏和嗜酸性粒细胞的独立研究计划 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 患者可以通过 OIT 成功脱敏，但许多患者会出现胃肠道副作用，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 胃肠道副作用的机制并 制定一种新的治疗策略来预防它们。为了实现这一目标，我们将进行一项子研究 在接受牛奶 OIT 联合或不联合 dupilumab 治疗的牛奶过敏患者中进行的安慰剂对照试验。期间 试验中，我们将连续监测嗜酸性粒细胞炎症、食管屏障功能障碍标志物和免疫 外周血和食道中的反应。为了支持赖特博士的职业发展，他将 获得细胞免疫学技能并完成专注于前沿的基础科学实习 临床样本的蛋白质组学分析。此外，他还将完成临床方面的正式教学课程。 研究设计、生物统计学和生物伦理学。赖特博士组建了一个指导委员会 由食物过敏、EoE、蛋白质组学、嗜酸性粒细胞生物学和 2 型免疫领域的国际专家组成 特别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。该提案结合了梅奥诊所研究环境的优势和正在进行的研究 与斯坦福大学的合作为进行上述培训提供了理想的环境 研究目标。在该计划结束时，赖特博士将拥有所需的技能和经验 过渡到独立并领导一个转化研究团队。该项目的顺利完成将 通过提供关键的服务，可能会对食物过敏患者的护理产生重大和持续的影响 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.