KLF4 and WNT5A in esophageal epithelial differentiation and stratification

项目摘要 在题为“食管上皮分化和分层中的KLF 4和WNT 5A”的申请中，我们寻求 明确食管上皮分化和分层的分子途径， 导致食管疾病的途径。PI是一名经验丰富的研究者和专家， Krüppel样因子（KLF），疾病的动物模型和食管鳞状细胞生物学，他是 由一流的研究团队，学院的智力环境和卓越的资源支持， 设施这项研究具有重要的意义，它体现了NIH的使命：“寻求根本的 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，如损伤后伤口愈合不良（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，这些疾病共同导致了 在美国和全世界，有相当大的发病率、死亡率和医疗保健负担。在 互补的方法，我们将采用新的小鼠模型，创新的二维和三维， 三维培养系统和下一代测序方法来测试KLF 4是 食管上皮分化和分层的关键调节因子， 正常上皮细胞的分层为深入了解这些过程是如何被破坏的提供了基础 如ESCC等疾病。为了解决这一假设，我们将探讨以下相互关联的具体问题。 目的：（1）通过对正常分化和分层的机制研究，明确正常分化和分层的途径。 KLF 4和WNT 5A（a）功能相互作用和（B）通过CDC 42和其他下游靶点;和（2）我们将 通过KLF 4和WNT 5A在体外和体内的功能研究， vivo. PI和他的团队拥有本申请中提出的所有技术的专业知识，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实质性的见解。 食管上皮分化、分层和癌变的途径，提供了 最终将这些知识转化为人类食管疾病。

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.