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，可引起组织重塑。食管 重塑包括纤维化和平滑肌肥大/功能障碍，其导致食管僵硬， 运动障碍临床症状包括呕吐、生长不良、吞咽困难、食物嵌塞和狭窄。我 以患者为导向的研究（POR）计划的重点是阐明的机制和临床影响， 儿童食管重塑在这里，我建议成为一个优秀的POR导师，以多样化的群体 来自多个学科的本科生/研究生、博士后研究员和初级教师培训生 并继续并扩展我的研究，以了解EoE作为一种炎症和 “机械传导”。在研究计划中，我测试了关于EoE基本机制的3个假设。的 首先是一个潜在的范式转移中心假设，即刚性基质改变了食管的功能， 成纤维细胞和平滑肌细胞与炎症一起并独立于炎症增殖EoE。这 具有临床意义，即对靶向炎症的治疗存在迫切的、未满足的临床需求- 独立重塑第二个假设是我目前POR的延伸，即粘附连接 E-cadherin蛋白是食管上皮细胞屏障功能丧失的关键， 显微镜是一种尖端的工具，将有助于我们理解屏障功能和 纳米水平的E-钙粘蛋白定位。第三个目的是评估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管炎症， 重塑与我的合作者和我们的学员一起，我开发和利用了创新的 从单细胞和完整的多细胞和功能性离体人转化的主要人模型 粘膜平台，以在体内分析的食管硬度和运动的儿童。我们的大，嗯- 表型EoE人群，我们能够不断地将我们的发现转化回患者。我参与了 我的每个目标中的学员，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研究人员 路径，为我的学员和我自己创建了一个正式的指导计划和团队，并整合了独特的资源 包括CTSA资助的临床和转化研究所。我有很好的记录 资助POR和培训学员，但需要保护的时间和进一步的教育，成为鼓舞人心的 我的导师。这是一个重要的目标，以维持研究和创造一个遗产的研究人员， 嗜酸性粒细胞性胃肠疾病（EGID）。我过去和现在的学员来自 过敏/免疫学，胃肠病学和生物工程，所有这些都致力于，并团结， 唯一的目标是解开EGID的机制，并将发现带回给患者。相结合 一个多学科的学员团队，一个优秀的研究和机构环境，以及一个强大的 指导计划是该提案成功的关键。

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.