Lysyl oxidase mediated fibrosis in eosinophilic esophagitis

赖氨酰氧化酶介导的嗜酸性食管纤维化

• 批准号: 9493462
• 负责人: Amanda Brooke Muir
• 金额: $ 15.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9493462
• 关键词: Albumins; Allergens; Allergic Disease; Allergic inflammation; Antibodies; Attenuated; Award; Biochemical; Bioethics; Biological Assay; Biological Models; Biopsy; Biopsy Specimen; Bolus Infusion; Cells; Chemicals; Childhood; Chronic; Chronic Disease; Cicatrix; Collagen; Complication; Data; Deglutition Disorders; Deposition; Development; Disease; Enzymes; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Epithelium; Esophageal; Esophageal Stenosis; Esophagus; Exposure to; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Food; Foundations; Future; Gastroenterologist; Genetic; Grant; Infiltration; Inflammation; Label; Laboratories; Lead; Matrix Metalloproteinases; Mediating; Mentors; Mesenchymal; Mus; Myofibroblast; Natural History; Oral; Patients; Phenotype; Physicians; Prevention; Production; Property; Protein-Lysine 6-Oxidase; Reaction; Research; Research Personnel; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Skin; TNF gene; Testing; Therapeutic; Tissues; Training; Transcriptional Regulation; Work; Writing; base; career; career development; chromatin immunoprecipitation; crosslink; cytokine; eosinophil; in vivo; inhibitor/antagonist; insight; knock-down; mouse model; novel; novel therapeutics; overexpression; prevent; public health relevance; research and development; skills; small hairpin RNA; small molecule inhibitor; treatment effect; treatment strategy

 DESCRIPTION (provided by applicant): The proposed training in the K08 application outlines an integrated plan of mentored research and career development activities as well as a specific strategy for this pediatric gastroenterologist to pursue an independent research career as a physician scientist. This award will allow her to refine existing and gain additional skills with te guidance of her mentors Drs. Rustgi and Nakagawa. She will pursue formal coursework as well as seminars in career development, bioethics, grant writing, and laboratory management. Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal infiltration of eosinophils. Esophageal fibrosis is the most serious complication of EoE, leading to dysphagia, food bolus impaction, and esophageal stricture. Fibrosis is defined as excess deposition of collagen leading to tissue stiffness. However, the quality of the collagen, meaning the extent of collagen cross-linking, may be just as important as the amount of collagen. Collagen cross-linking by the enzyme lysyl oxidase (LOX) enhances stiffness within the tissue. Increased tissue stiffness may support a positive feedback loop that increases fibrosis, since fibroblasts are known to transdifferentiate into activated myofibroblasts upon contact with a stiff matrix. Preliminary data suggest that cross-talk between esophageal epithelial cells and esophageal fibroblasts, specifically through the cytokine TNFa, enhances expression of LOX. In addition, LOX expression is upregulated in patients with active EoE in biopsy samples. Based on these findings, the overall hypothesis is that LOX is a critical modulator of fibrosis in EoE and that it functional properties are mediated in part through specific epithelial-fibroblast interactions. Using an established organotypic culture model system, the investigator will define how epithelial derived LOX enhances myofibroblast activation and increases tissue stiffness (Aim 1). She will determine the mechanism in which TNFa induces LOX expression utilizing genetic and chemical inhibition. She will further delve into the signaling pathway of TNFa and determine the mechanism of signaling that ultimately results in LOX expression (Aim 2). Lastly, we will look in vivo at the role of LOX in a chronic mouse model of EoE. Through chemical inhibition, she will determine the effect of LOX inhibition on fibroblast activation and function (Aim 3). She anticipates that results from these studies will define LOX's role in EoE fibrosis and will provide the foundation for future studies with translational applications in the management and therapy of EoE. These studies will elucidate novel mechanisms of LOX in EoE and have the potential to contribute significantly to understanding of fibrosis.

 描述（由应用程序提供）：K08应用程序中提议的培训概述了指导研究和职业发展活动的综合计划，以及该儿科胃肠病学家的特定策略，以从事物理科学家从事独立的研究职业。该奖项将使她能够在导师DR的指导下完善现有的技能并获得其他技能。 Rustgi和Nakagawa。她将在职业发展，生物伦理学，赠款写作和实验室管理中购买正式的课程以及下水道。嗜酸性食管炎（EOE）是一种以食道嗜酸性粒细胞浸润为特征的过敏性疾病。食管纤维化是EOE最严重的并发症，导致吞咽困难，食物注射和食管狭窄。纤维化被定义为胶原蛋白的过量沉积，导致组织刚度。但是，胶原蛋白的质量（意味着胶原蛋白交联的程度）可能与胶原蛋白的数量一样重要。胶原蛋白通过酶氧化酶（LOX）的交联可增强组织内的刚度。增加的组织刚度可能会支持阳性反馈回路，从而增加纤维化，因为已知成纤维细胞在与刚性基质接触后将其转化为活化的肌纤维细胞。初步数据表明，食管上皮细胞和食管成纤维细胞之间的串扰，特别是通过细胞因子TNFA增强了LOX的表达。此外，在活检样品中活跃EOE的患者中，LOX表达进行了更新。基于这些发现，总体假设是LOX是EOE中纤维化的关键调节剂，它的功能性能部分通过特定的上皮细胞相互作用来部分介导。使用已建立的有机培养模型系统，研究人员将定义上皮衍生的LOX如何增强肌纤维细胞的激活并增加组织刚度（AIM 1）。她将确定TNFA利用遗传和化学抑制作用的LOX表达的机制。她将进一步研究TNFA的信号传导途径，并确定最终导致LOX表达的信号传导机制（AIM 2）。最后，我们将在体内看一下LOX在EOE的慢性小鼠模型中的作用。通过化学抑制，她将确定LOX抑制对成纤维细胞激活和功能的影响（AIM 3）。她预计这些研究的结果将定义LOX在EOE纤维化中的作用，并将提供 未来研究的基础，在EOE的管理和治疗中进行了翻译应用。这些研究将阐明EOE中LOX的新机制，并有可能为理解纤维化做出重大贡献。