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

• 批准号: 9889959
• 负责人: JONATHAN P KATZ
• 金额: $ 36.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9889959
• 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; Epithelium; 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

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.

项目概要 在这份题为“食管上皮分化和分层中的 KLF4 和 WNT5A”的申请中，我们寻求 定义食管上皮分化和分层的分子途径以及扰动 这些途径导致食管疾病。 PI 是一位经验丰富的调查员和专家 Krüppel 样因子 (KLF)、疾病动物模型和食管鳞状细胞生物学，他是 拥有一流的研究团队、学院般的智力环境以及卓越的资源和支持 设施。拟议的研究非常重要，它解决了 NIH 的使命“寻求根本性的 关于生命系统的性质和行为的知识”并提供翻译的潜力 食管疾病，例如受伤后伤口愈合不良（例如辐射、感染、嗜酸性粒细胞增多症） 食管炎）和食管鳞状细胞癌（ESCC）等疾病，它们共同导致 美国和世界各地的发病率、死亡率和医疗负担相当大。在 互补的方法，我们将采用新颖的小鼠模型，创新的二维和三维 维度培养系统和下一代测序方法来检验 KLF4 的假设 食管上皮分化和分层的关键调节因子，研究分化和分层 正常上皮细胞的分层为深入了解这些过程如何被破坏提供了基础 患有食管鳞癌等疾病时。为了解决这个假设，我们将追求以下相互关联的具体内容 目的：（1）我们将通过机制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 和其他下游靶标； (2) 我们将 通过体外和体内 KLF4 和 WNT5A 的功能研究描绘 ESCC 的分子基础 体内。 PI 和他的团队拥有本应用程序中提出的所有技术的专业知识，并且所有模型都是 目前在手。总之，我们预计这些研究将为监管提供深入的见解 食管上皮分化、分层和癌变的途径，为食管上皮分化、分层和癌变提供了潜力 最终将这些知识转化为人类食管疾病。