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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.

项目摘要这项提议的首要目标是了解上皮细胞对食管癌的作用。炎症和组织损伤的机制研究的关键炎症介质抑制剂的核因子κ-B激酶β亚基（IKKβ）。这一建议的意义在于：1）食管疾病，这是美国和全世界的重大负担，和2）中央上皮IKKβ信号在调节多种生物过程中的作用，如炎症，免疫、细胞存活和细胞生长。PI是早期研究者他是上皮炎症和损伤、炎症介质、疾病动物模型和上皮生物学，并由一流的研究团队支持，并辅以专家合作者。在这里，我们将利用新的小鼠模型和利用3D培养系统的补充体外系统，为了验证上皮IKKβ信号的激活产生促炎性、促炎性、增殖，促血管生成的环境，倾向于发展食管疾病，鳞状细胞发育不良和癌症。为了探索这些过程，我们将进行三个相互关联的具体目标。在目标1中，我们将确定STAT 3激活和IKKβ信号转导在人卵巢癌中的功能相互作用。食管上皮细胞的增殖反应。这将使用具有两种活性的小鼠来进行。 IKKb和STAT 3缺失以及三维（3D）小鼠食管类器官。在目标2中，我们定义上皮细胞IKKβ信号在从正常细胞转变为正常细胞过程中上皮-内皮细胞相互作用中的作用食管发育不良。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，和3D血管网络形成测定。在Aim中 3、我们将研究上皮IKKβ信号在食管上皮炎症反应中的作用。细胞从正常状态过渡到食管发育不良。这将是新的转基因用4-NQO处理的食管上皮IKKβ缺失小鼠模型。这些互补这些方法将证实和扩展我们的初步数据和我们最近发表在《胃肠病学。此外，拟议的研究将得到一流的和大学的知识分子的支持，环境和特殊的资源和设施提供给PI。我们预计这些研究将提供对调节正常食管上皮稳态的因素的深入了解，微环境，以及良性和恶性食管疾病中被破坏的途径。