KLF4 and WNT5A in esophageal epithelial differentiation and stratification

KLF4和WNT5A在食管上皮分化和分层中的作用

基本信息

批准号：
10374840
负责人：
JONATHAN P KATZ
金额：
$ 36.56万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374840
关键词：
3-Dimensional Ablation Address Animal Disease Models Behavior CDC42 gene Cancer cell line Cell Differentiation process Cell Line Cell Polarity Cell physiology Cells Cellular biology ChIP-seq DNA Data Diagnosis Dimensions Disease Down-Regulation Dysplasia Environment Eosinophilic Esophagitis Epithelial Epithelial Cells Esophageal Diseases Esophageal Squamous Cell Esophageal Squamous Cell Carcinoma Esophagus Foundations Gastrointestinal tract structure Genetic Models Genetic Transcription Growth Hand Healthcare Homeostasis Human Hypermethylation In Vitro Infection Injury Knowledge Lead Link Maintenance Mediating Mediator of activation protein Mission Modeling Molecular Morbidity - disease rate Mus Natural regeneration Nature Normal tissue morphology Organ Organism Oropharyngeal Pathway interactions Process Publishing Radiation Regulatory Pathway Research Research Personnel Resources Role Skin Squamous Cell Squamous Differentiation Squamous Epithelium Stratification Stratified Epithelium Sum System Techniques Testing Tissues Translations United States United States National Institutes of Health WNT5A gene Work base carcinogenesis cell motility cell type esophageal squamous cell cancer esophageal squamous cell carcinogenesis experience experimental study gastrointestinal epithelium improved in vivo innovation insight keratinocyte keratinocyte differentiation knowledge translation loss of function migration mortality mouse model next generation sequencing novel postnatal repaired response to injury rho GTP-Binding Proteins skin barrier stem cells three dimensional cell culture transcription factor transcriptome sequencing tumorigenesis two-dimensional wound healing

3-Dimensional Ablation Address Animal Disease Models Behavior CDC42 gene Cancer cell line Cell Differentiation process Cell Line Cell Polarity Cell physiology Cells Cellular biology ChIP-seq DNA Data Diagnosis Dimensions Disease Down-Regulation Dysplasia Environment Eosinophilic Esophagitis Epithelial Epithelial Cells Esophageal Diseases Esophageal Squamous Cell Esophageal Squamous Cell Carcinoma Esophagus Foundations Gastrointestinal tract structure Genetic Models Genetic Transcription Growth Hand Healthcare Homeostasis Human Hypermethylation In Vitro Infection Injury Knowledge Lead Link Maintenance Mediating Mediator of activation protein Mission Modeling Molecular Morbidity - disease rate Mus Natural regeneration Nature Normal tissue morphology Organ Organism Oropharyngeal Pathway interactions Process Publishing Radiation Regulatory Pathway Research Research Personnel Resources Role Skin Squamous Cell Squamous Differentiation Squamous Epithelium Stratification Stratified Epithelium Sum System Techniques Testing Tissues Translations United States United States National Institutes of Health WNT5A gene Work base carcinogenesis cell motility cell type esophageal squamous cell cancer esophageal squamous cell carcinogenesis experience experimental study gastrointestinal epithelium improved in vivo innovation insight keratinocyte keratinocyte differentiation knowledge translation loss of function migration mortality mouse model next generation sequencing novel postnatal repaired response to injury rho GTP-Binding Proteins skin barrier stem cells three dimensional cell culture transcription factor transcriptome sequencing tumorigenesis two-dimensional wound healing

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项目摘要

PROJECT SUMMARY In this application entitled “KLF4 and WNT5A in esophageal epithelial differentiation and stratification,” we seek to define the molecular pathways of esophageal epithelial differentiation and stratification and the perturbations of these pathways that lead to esophageal diseases. The PI is an experienced investigator and expert in the Krüppel-like factors (KLFs), animal models of disease, and esophageal squamous cell biology, and he is supported by a superb research team, a collegial intellectual environment, and exceptional resources and facilities. The proposed research is highly significant, addressing the NIH mission of “seeking fundamental knowledge about the nature and behavior of living systems” and offering the potential for translation to esophageal disorders such as defective wound healing after injury (e.g. radiation, infection, eosinophilic esophagitis) and diseases such as esophageal squamous cell cancer (ESCC), which together account for considerable morbidity, mortality, and healthcare burden in the United States and throughout the world. In complementary approaches, we will employ novel mouse models, innovative two-dimensional and three- dimensional culture systems, and next generation sequencing approaches to test the hypothesis that KLF4 is a key regulator of esophageal epithelial differentiation and stratification and that studies of differentiation and stratification in normal epithelia provide the foundation for insights into how these processes are disrupted during diseases such as ESCC. To address this hypothesis, we will pursue the following interrelated Specific Aims: (1) We will define the pathways of normal differentiation and stratification through mechanistic studies of KLF4 and WNT5A (a) functional interactions and (b) via CDC42 and other downstream targets; and (2) We will delineate the molecular underpinnings of ESCC through functional studies of KLF4 and WNT5A in vitro and in vivo. The PI and his team have expertise in all techniques proposed in this application, and all models are currently in hand. In sum, we anticipate that these studies will provide substantial insight into the regulatory pathways of esophageal epithelial differentiation, stratification, and carcinogenesis, offering the potential for eventual translation of this knowledge to human esophageal diseases.

项目摘要在此应用中，我们寻求“食管上皮分化和分层中的KLF4和WNT5A”，我们寻求定义食道上皮分化和分层的分子途径以及扰动这些导致食管疾病的途径。 PI是经验丰富的研究员和专家 Krüppel样因子（KLF），疾病动物模型和食管鳞状细胞生物学，他是由一支精湛的研究团队，合作的智力环境以及卓越的资源以及设施。拟议的研究非常重要，涉及NIH的使命“寻求基本关于生活系统的性质和行为的知识”，并提供翻译的潜力食管疾病，例如损伤后伤口愈合缺陷（例如辐射，感染，嗜酸性粒细胞食管炎）和食管鳞状细胞癌（ESCC）等疾病，共同考虑美国及其全世界的发病率，死亡率和医疗保健伯恩（Burnen）。在完全接近，我们将采用新颖的小鼠模型，创新的二维和三维的模型维度培养系统以及下一代测序方法，以测试KLF4是食管上皮分化和分层的关键调节剂，以及分化和研究的研究正常上皮中的分层为洞悉这些过程如何破坏的基础在ESCC等疾病期间。为了解决这一假设，我们将追求以下相互关联的特定目的：（1）我们将通过机械研究来定义正常分化和分层的途径 KLF4和WNT5A（A）功能相互作用以及（B）通过CDC42和其他下游目标；（2）我们将通过在体外和IN中的KLF4和WNT5A的功能研究来描述ESCC的分子基础体内。 PI和他的团队在本应用程序中提出的所有技术方面都有专业知识，所有模型均为目前在场。总而言之，我们预计这些研究将为监管提供大量见解食道上皮分化，分层和癌变的途径，为潜在的潜力最终将这种知识转化为人类食管疾病。