Structural and molecular markers for detection and monitoring of pediatric fibrostenotic Eosinophilic Esophagitis

项目总结 这份K23提案描述了卡利斯博士为期5年的职业发展和研究计划 科罗拉多大学医学院(CU SOM)助理教授梅纳德-卡彻和一位 科罗拉多州儿童医院胃肠道嗜酸性疾病项目的专家。这 K23将为候选人提供必要的支持，以便在以患者为导向的研究中开始成功的职业生涯 嗜酸性胃肠道疾病。根据之前的研究经验和初步数据，她是 儿童嗜酸性食管炎(EoE)纤维狭窄表型的研究 免费的高级评估工具，包括功能管腔阻抗(FliP)和基因 分析。此K23应用程序包括以下组件： 研究：EoE是一种慢性过敏原引发的食道疾病，已成为最常见的 儿童和成人吞咽问题的常见原因。食道狭窄，又称纤维狭窄 EoE(FS-EoE)，已成为EoE的主要并发症。这种表型的临床结果更差。 而且可能对目前的治疗方法更具抵抗力。有证据表明，临床上有意义的评估 目前的临床评估工具不太可能捕捉到FS食道。替代策略有 需要评估食道功能和粘膜以外重塑的影响才能推进 了解疾病发生机制，改进靶向治疗。Flip和Flip的内窥镜评估 内窥镜超声(EUS)可以提供这种方法。与RNA测序配对鉴定新的FS-EoE 相关基因，这一建议将为FS-EoE表型的研究提供关键的进展。 我们假设食道的结构测量和组织的分子标记 在儿科受试者中，重塑将区分FS-EoE和非FS-EoE。我们将确定其膨胀性 儿童FS-EoE与炎症性非FS-EoE的比较及与其他临床特征的关系 对于EoE(目标1)，确定定义儿童FS-EoE(目标2)的基因特征，并评估结构的变化 和药物治疗反应的分子特征(目标3)。这项新研究的结果将提供 通过识别以前从未报道过的结构、功能和分子签名产生重大影响 儿科FS-EoE。 职业发展：Menard-Katcher博士的短期目标是获得成为 一名拥有R01资金的独立调查员，以解决将导致更好地 对EoE的发病机制和治疗的认识。这一培训奖项将使 在EoE表型的内窥镜评估、下一代序列解释和早期 潜在生物标志物的评估。Glenn T.Furuta医学博士是这项提案的主要导师，他是一位全国性的 嗜酸性胃肠道疾病(EGID)领域的知名研究员和临床专家。忠告 共同导师委员会将为拟议研究的成功提供额外的关键指导 候选人向独立的过渡。此外，Menard-Katcher博士还将继续进行说教培训，包括 完成临床科学硕士学位，以支持她的目标。

PROJECT SUMMARY This K23 proposal describes a 5-year career development and research program for Dr. Calies Menard-Katcher, an Assistant Professor at the University of Colorado School of Medicine (CU SOM) and a subspecialist within the Gastrointestinal Eosinophilic Diseases Program at Children's Hospital Colorado. This K23 will provide the candidate necessary support to launch a successful career in patient-oriented research in eosinophilic gastrointestinal diseases. Building on prior research experience and preliminary data, she is investigating the fibrostenotic phenotype of pediatric Eosinophilic Esophagitis (EoE) by means of complimentary and advanced assessment tools including functional luminal impedance (FLIP) and gene analyses. This K23 application includes the following components: Research: EoE, a chronic, allergen triggered esophageal disease has emerged as one of the most common causes of swallowing problems in children and adults. Esophageal stricture, also termed fibrostenotic EoE (FS-EoE), has emerged as the major complication of EoE. This phenotype has worse clinical outcomes and may be more resistant to current treatments. Evidence suggests that clinically meaningful assessment of the FS esophagus is unlikely to be captured by current clinical assessment tools. Alternative strategies are needed to assess esophageal function and the impact of remodeling beyond the mucosa to advance understanding of disease mechanism and improve targeted therapies. Endoscopic assessment with FLIP and endoscopic ultrasound (EUS) can provide this approach. Paired with RNA sequencing to identify novel FS-EoE associated genes, this proposal will provide critical advancement in the study of the FS-EoE phenotype. We hypothesize structural measurements of the esophagus and molecular markers of tissue remodeling will distinguish FS-EoE from non-FS EoE in pediatric subjects. We will determine distensibility of the esophagus in pediatric FS-EoE compared to inflammatory non-FS-EoE in relation to other clinical features of EoE (Aim 1), identify a gene signature defining pediatric FS-EoE (Aim 2) and assess changes in structural and molecular features in response to medical treatment (Aim 3). Results from this novel research will provide significant impact by identifying never before reported structural, functional and molecular signatures of pediatric FS-EoE. Career Development: Dr. Menard-Katcher's short-term goal is to obtain the training required to become an independent investigator with R01 funding to address important questions that will lead to better understanding of the pathogenesis and management of EoE. This training award will allow for development of expertise in endoscopic assessment of EoE phenotypes, next generation sequence interpretation and early assessment of potential biomarkers. Glenn T. Furuta, MD, the primary mentor for this proposal, is a nationally recognized investigator and clinical expert in the field of eosinophilic GI diseases (EGIDs). An advisory committee of co-mentors will provide additional key guidance for the success of the proposed research and the candidate's transition to independence. In addition Dr. Menard-Katcher will continue didactic training, including completion of a Master's in Clinical Sciences, to support her goals.