Cytoprotective pathways in esophageal squamous epithelia

食管鳞状上皮的细胞保护途径

• 批准号: 10660394
• 负责人: JONATHAN P KATZ
• 金额: $ 59.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660394
• 关键词: Address; Alcohols; Apoptosis; BAX gene; BCL2 gene; Binding; Cancer Etiology; Cell Cycle Arrest; Cell Fate Control; Cell Line; Cells; Cessation of life; Critical Pathways; Cytoprotection; DNA Sequence Alteration; Data; Development; Disease; Epithelial Cells; Epithelium; Esophageal Diseases; Esophageal Squamous Cell; Esophageal mucous membrane; Esophagus; Event; Exposure to; Genetic Transcription; Genotoxic Stress; Health; Homeostasis; Human; Individual; Inflammation; Inflammatory; Injury; Irritants; Kruppel-like transcription factors; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Molecular; Mutate; Mutation; Neoplasms; Outcome; Pathway interactions; Pattern; Physiological; Play; Proliferating; Proto-Oncogene Proteins c-akt; Regulation; Regulatory Pathway; Smoke; Smoking; Squamous Epithelium; Stress; TP53 gene; Testing; Tobacco; Tumor Suppressor Proteins; carcinogenesis; cell transformation; cigarette smoke; cytokine; environmental stressor; esophageal squamous cell cancer; genome-wide; genotoxicity; keratinocyte; migration; mouse model; mutant; physiologic stressor; prevent; repaired; response; response to injury; stressor; three dimensional cell culture; three-dimensional modeling; tumor progression; ultraviolet irradiation

PROJECT SUMMARY Disorders of the esophagus are significant health problems in the U.S. and throughout the world, and esophageal cancer, of which more than 80% is esophageal squamous cell cancer (ESCC), is the 6th most common cause of cancer death worldwide. Exposure of esophageal squamous epithelial cells (keratinocytes) to injurious agents such as cigarette smoke and alcohol predisposes to ESCC, and yet malignant transformation of a single esophageal keratinocyte even in response to such stressors is rare. Thus, important cytoprotective mechanisms must exist in normal esophageal keratinocytes to respond to these insults and prevent malignant transformation of these cells. To date, these mechanisms are not well understood. Here, we propose to delineate important cytoprotective pathways in esophageal keratinocytes, focusing on the key transcriptional regulator Krüppel-like factor 5 (KLF5) and the tumor suppressor p53 in the response to physiologic stress. In normal epithelia, KLF5 functions to promote proliferation and migration and to inhibit inflammation, and in new preliminary data, we define critical functions for KLF5 and wild-type p53 in the cellular responses to exogenous stress in non-transformed esophageal keratinocytes and demonstrate that mutant p53 modulates genome-wide binding of KLF5, thereby altering the targets and pathways governed by KLF5 in this context. Our overarching hypothesis is that KLF5 and p53 are a molecular rheostat, coordinately regulating esophageal squamous epithelial responses to exogenous stressors, and that disruption of this regulation underlies defective cell repair and ESCC. To test this hypothesis, we will pursue the following interrelated Specific Aims: 1. We will define KLF5-p53 targets and function in normal keratinocytes with exogenous stress; 2. We will determine mutant p53 alterations of genome-wide KLF5 binding in homeostasis and stress; 3. We will delineate the functions of KLF5 and p53 in esophageal mucosal injury resulting from smoking and alcohol. Overall, the proposed studies provide a framework to understand the mechanisms by which normal esophageal keratinocytes respond to environmental stresses and the perturbations of these responses that underlie malignant transformation and progression in the squamous esophagus.

项目摘要 食管疾病是美国和全世界的重大健康问题， 食管癌，其中超过80%是食管鳞状细胞癌（ESCC），是第6大 是全球癌症死亡的常见原因。食管鳞状上皮细胞（角质形成细胞）的暴露 有害物质，如香烟烟雾和酒精，易患食管癌，但恶性 即使在对这种应激源的反应中，单个食管角质形成细胞的转化也是罕见的。因此，重要 细胞保护机制必须存在于正常食管角质形成细胞中以响应这些损伤， 防止这些细胞的恶性转化。到目前为止，这些机制还没有得到很好的理解。在这里， 我们建议描绘食管角化细胞中重要的细胞保护途径，重点是关键的 转录调节因子Krüppel样因子5（KLF 5）和肿瘤抑制因子p53在对 生理应激在正常上皮细胞中，KLF 5的功能是促进增殖和迁移，并抑制增殖和迁移。 在新的初步数据中，我们定义了KLF 5和野生型p53在细胞内的关键功能。 非转化食管角化细胞对外源性应激的反应，并证明突变体 p53调节KLF 5的全基因组结合，从而改变KLF 5在细胞内的靶点和途径。 这个背景。我们的首要假设是KLF 5和p53是一个分子变阻器，协调 调节食管鳞状上皮对外源性应激的反应， 调节是缺陷细胞修复和ESCC的基础。为了验证这一假设，我们将进行以下研究： 具体目标：1。我们将确定KLF 5-p53的目标和功能，在正常角质形成细胞， 外源胁迫; 2.我们将确定突变p53改变全基因组KLF 5结合在稳态 压力; 3。我们将阐述KLF 5和p53在食管粘膜损伤中的作用， 吸烟和酒精。总的来说，拟议的研究提供了一个框架，以了解机制， 正常食管角化细胞对环境应激的反应以及这些应激的扰动， 鳞状食管恶性转化和进展的基础反应。