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.

项目总结 食道疾病在美国和世界各地都是严重的健康问题， 食道癌，其中80%以上是食道鳞状细胞癌(ESCC)，排在第六位 世界范围内癌症死亡的常见原因。食道鳞状上皮细胞(角质形成细胞)的暴露 如香烟烟雾和酒精等有害物质易患ESCC，但却是恶性的 单个食道角质形成细胞的转化即使是对这种应激源的反应也是罕见的。因此，重要的是 正常的食道角质形成细胞必须存在细胞保护机制才能对这些侮辱和 防止这些细胞的恶性转化。到目前为止，这些机制还没有被很好地理解。这里, 我们建议在食道角质形成细胞中描述重要的细胞保护途径，重点是关键 转录调节因子Krf5和肿瘤抑制因子P53在对 生理压力。在正常的上皮细胞中，KLF5的功能是促进增殖和迁移，并抑制 炎症，在新的初步数据中，我们定义了KLF5和野生型p53在细胞中的关键功能 未转化的食道角质形成细胞对外源应激的反应 P53调控KLF5的全基因组结合，从而改变KLF5调控的靶点和通路 这一背景。我们的主要假设是KLF5和P53是一个分子变阻器，协同作用 调控食道鳞状上皮对外源性应激源的反应，以及这种反应的破坏 调控是缺陷细胞修复和ESCC的基础。为了验证这一假设，我们将进行以下工作 相关的特定目标：1.我们将确定KLF5-P53在正常角质形成细胞中的靶点和功能 外源应激；2.我们将在动态平衡中确定全基因组KLF5结合的突变型p53的变化 我们将阐明KLF5和P53在食道粘膜损伤中的作用。 吸烟和酗酒。总体而言，拟议的研究提供了一个框架，通过 哪些正常的食道角质形成细胞对环境压力和这些细胞的扰动做出反应 鳞状食道恶变和进展的基础反应。