Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders

项目摘要 EoE是一种新发现的慢性、抗原驱动的过敏性疾病，会导致组织重塑。食道 重塑包括纤维化和平滑肌肥大/功能障碍，导致食道僵硬和 运动障碍。临床症状包括呕吐、生长不良、吞咽困难、食物阻塞和狭窄。我的 以患者为中心的研究(POR)计划侧重于阐明心绞痛的机制和临床影响。 儿童食道重塑。在此，我建议成为一个不同群体的杰出POR导师 来自多个学科的本科生/研究生、博士后研究员和初级教员实习生 并继续和扩展我的研究，以理解EoE作为一种炎症和 “机械转导”。在研究计划中，我检验了三个关于EoE基本机制的假设。这个 首先是一种潜在的范式转移的中心假设，即刚性基质改变食道功能 成纤维细胞和平滑肌细胞与炎症一起繁殖EoE，并且不依赖于炎症。这 具有临床意义，即针对炎症的治疗存在迫切的、未得到满足的临床需求- 独立改建。第二个假设是我目前POR的一个扩展，即粘附结 E-钙粘附素在食道上皮细胞屏障功能丧失和超分辨中起关键作用 显微镜是一种尖端工具，它将有助于我们理解屏障功能和 E-钙粘附素在纳米水平的定位。第三个目标是评估EoE严重程度的性别差异 假设男性成纤维细胞本质上更倾向于食道炎和 改建。与我的合作者和我们的共同导师一起，我开发并利用了创新 从单细胞和完整的多细胞及有功能的体外人过渡的初步人类模型 黏膜平台对儿童食道僵硬和运动能力的活体分析。带着我们巨大的，好的- 在表型EoE人群中，我们能够不断地将我们的发现传回给患者。我参与了 在我的每一个目标中，指导对象都制定了一个正式的计划，在实验室、诊所和职业生涯中培训初级调查人员 Path，为我和我的学员创建了一个正式的指导计划和团队，并整合了独特的资源 在加州大学圣地亚哥分校，包括CTSA资助的临床和翻译研究所。我有很好的记录 资助POR和培训学员，但需要受保护的时间和继续教育才能成为鼓舞人心的 我想象中的导师。这是维持研究和创造研究遗产的一个重要目标 嗜酸性胃肠道疾病(EGID)。我过去和现在的受训者来自 过敏/免疫学、胃肠病学和生物工程学，所有这些学科都致力于并由 唯一的目标是解开EGID的机制，并将发现带回给患者。组合在一起 一个多学科的指导团队，卓越的研究和机构环境，以及强大的 指导计划是这项提议成功的关键。

Project Summary EoE is a newly recognized chronic, antigen driven allergic disease that causes tissue remodeling. Esophageal remodeling includes fibrosis and smooth muscle hypertrophy/dysfunction that leads to esophageal rigidity and dysmotility. Clinical symptoms include vomiting, poor growth, dysphagia, food impactions, and strictures. My patient oriented research (POR) program focuses on elucidating the mechanisms and clinical impacts of esophageal remodeling in children. Herein I propose to become an outstanding POR mentor to a diverse group of undergraduate/graduate students, postdoctoral fellows, and junior faculty trainees from multiple disciplines and to continue and extend my research to understanding EoE as a disease of both inflammation and “mechanotransduction”. In the Research Plan, I test 3 hypotheses on the fundamental mechanisms of EoE. The first is a potentially paradigm shifting central hypothesis that a rigid matrix alters the function of esophageal fibroblasts and smooth muscle cells to propagate EoE together with, and independently of, inflammation. This has the clinical implication that there is a pressing, unmet clinical need for therapies that target inflammation- independent remodeling. The second hypothesis, an extension of my current POR, is that the adherens junction protein, E-cadherin, is pivotal in the loss of esophageal epithelial cell barrier function and that super resolution microscopy is a cutting-edge tool that will aid our understanding of the interaction between barrier function and E-cadherin localization at the nanometer level. The third aim is to evaluate gender differences in EoE severity with the hypothesis that male fibroblasts are intrinsically more biased to esophageal inflammation and remodeling. Together with my collaborators and our co-mentees, I have developed and utilized innovative primary human models that transition from single cells and intact multicellular and functional ex vivo human mucosal platforms to an in vivo analyses of esophageal rigidity and motility in children. With our large, well- phenotyped EoE population, we are able to continuously translate our findings back to the patient. I have involved mentees in each of my aims, developed a formal plan to train junior investigators in the lab, clinic and career path, created a formal mentoring plan and team for my mentees and myself, and integrated the unique resources at UCSD including the CTSA funded Clinical and Translational Research Institute. I have a strong record of funded POR and training mentees but require the protected time and further education to become the inspiring mentor I envision. This is an important goal for sustaining research and creating a legacy of investigators in eosinophilic gastrointestinal disorders (EGIDs). My past and current group of mentees are from Allergy/Immunology, Gastroenterology, and Bioengineering, all of whom are dedicated to, and united by, the singular goal of unraveling mechanisms of EGIDs and bringing the findings back to the patient. The combination of a multidisciplinary mentee team, an outstanding research and institutional environment, and a strong mentoring plan are key to the success of this proposal.