Molecular Mechanisms of Epithelial Contribution to Esophageal Inflammation and Tissue Repair

上皮细胞对食管炎症和组织修复贡献的分子机制

基本信息

批准号：
10359705
负责人：
MARIE-PIER TETREAULT
金额：
$ 35.55万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359705
关键词：
3-Dimensional Animal Disease Models Barrett Esophagus Benign Biological Assay Biological Process Biology Blood Vessels CXCL9 gene Cancer Etiology Cell Communication Cell Proliferation Cell Survival Cells Cessation of life ChIP-seq Complement Complex Data Development Diagnosis Disease Dysplasia Endothelial Cells Environment Epithelial Epithelial Cells Equilibrium Esophageal Adenocarcinoma Esophageal Diseases Esophageal Intraepithelial Neoplasia Esophageal Squamous Cell Esophagitis Esophagus Gastroenterology Gastroesophageal reflux disease Gastrointestinal tract structure Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Homeostasis I Kappa B-Alpha Immune Immunity In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Knowledge Lead Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Modeling Molecular Mus NF-kappaB-inducing kinase Nitroquinolines Nuclear Organoids Oxides Pathogenesis Pathway interactions Patients Phenotype Play Prevalence Process Production Publications Regulation Research Research Personnel Resources Role Signal Transduction Skin Squamous Cell Stat3 protein Stratified Epithelium Survival Rate System TNF gene Testing Tissues Transgenic Mice United States Visit angiogenesis cancer cell cancer therapy cell growth cell type chemokine cytokine factor A improved in vivo insight mouse model new therapeutic target notch protein novel novel strategies recruit repaired response three dimensional cell culture tissue injury tissue repair tumor microenvironment

项目摘要

PROJECT SUMMARY The overarching goal of this proposal is to understand the contribution of the epithelium to esophageal inflammation and tissue injury through mechanistic studies of the key inflammatory mediator inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). The significance of this proposal lies in 1) the prevalence of esophageal disorders, which are a significant burden in the U.S. and throughout the world and 2) the central role of epithelial IKKβ signaling in the regulation of diverse biological processes, such as inflammation, immunity, cell survival, and cell growth in numerous tissues and cell types. The PI is an early-stage investigator who is an expert in epithelial inflammation and injury, inflammatory mediators, animal models of disease, and epithelial biology, and is supported by a superb research team, complemented by expert collaborators. Here, we will take advantage of new mouse models and complementary in vitro systems utilizing 3D culture system to test the hypothesis that activation of epithelial IKKβ signaling produces a pro-inflammatory, pro- proliferative, pro-angiogenic milieu that tips the balance towards the development esophageal diseases such as squamous cell dysplasia and cancer. To explore these processes, we will undertake three interrelated Specific Aims. In Aim 1, we will determine the functional interplay of STAT3 activation and IKKβ signaling in the proliferative response of esophageal epithelial cells. This will be undertaken using mice with both active IKKb and STAT3 deletion, and three-dimensional (3D) mouse esophageal organoids. In Aim 2, we will define the role of epithelial IKKβ signaling in epithelial-endothelial cell interactions during the transition from a normal state to esophageal dysplasia. Here, we will utilize a novel transgenic mouse model with esophageal epithelial IKKβ deletion treated with 4-Nitroquinoline 1-oxide (4-NQO), and 3D vascular network formation assay. In Aim 3, we will investigate the role of epithelial IKKβ signaling in the inflammatory response of esophageal epithelial cells during the transition from a normal state to esophageal dysplasia. This will be undertaken new transgenic mouse model of esophageal epithelial IKKβ deletion that is treated with 4-NQO. These complementary approaches will confirm and extend the findings from our Preliminary Data and from our recent publication in Gastroenterology. Moreover, the proposed research will be supported by the superb and collegial intellectual environment and the exceptional resources and facilities available to the PI. We anticipate that these studies will provide insight into the factors that regulate normal esophageal epithelial homeostasis, the microenvironment, and the pathways that are disrupted in esophageal diseases, both benign and malignant.

项目概要该提案的总体目标是了解上皮对食管的贡献通过核关键炎症介质抑制剂的机制研究炎症和组织损伤因子kappa-B激酶亚基β（IKKβ）这一提议的意义在于1）普遍存在。食管疾病，这在美国和全世界都是一个重大负担，2) 中枢上皮 IKKβ 信号传导在多种生物过程调节中的作用，例如炎症、 PI 是众多组织和细胞类型中的免疫、细胞存活和细胞生长的早期研究者。他是上皮炎症和损伤、炎症介质、疾病动物模型等领域的专家上皮生物学，并得到了优秀研究团队的支持，并得到了专家合作者的补充。我们将利用新的小鼠模型和利用 3D 培养系统的互补体外系统测试上皮 IKKβ 信号传导的激活会产生促炎、促- 增殖的、促血管生成的环境，可以平衡食管疾病的发展，例如为了探索这些过程，我们将进行三个相互关联的过程。具体目标在目标 1 中，我们将确定 STAT3 激活和 IKKβ 信号传导的功能相互作用。这将使用具有两种活性的小鼠来进行。 IKKb 和 STAT3 缺失以及三维 (3D) 小鼠食管类器官在目标 2 中，我们将定义。上皮 IKKβ 信号在上皮-内皮细胞从正常状态转变过程中相互作用中的作用在这里，我们将利用一种新型的食管上皮转基因小鼠模型。用 4-硝基喹啉 1-氧化物 (4-NQO) 处理 IKKβ 缺失，并进行 3D 血管网络形成测定。 3、我们将研究上皮IKKβ信号在食管上皮炎症反应中的作用细胞从正常状态转变为食管发育不良，这将进行新的转基因。用 4-NQO 治疗的食管上皮 IKKβ 缺失的小鼠模型。方法将确认并扩展我们的初步数据和我们最近发表的研究结果此外，拟议的研究将得到优秀的大学知识分子的支持。我们期望这些研究能够得到环境以及 PI 可用的特殊资源和设施。将深入了解调节正常食管上皮稳态的因素，微环境以及食管良性和恶性疾病中被破坏的途径。