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 食道疾病在美国和世界各地都是重大健康问题， 食道癌，其中80％以上是食道鳞状细胞癌（ESCC），是第六名 全球癌症死亡的常见原因。暴露食管鳞状上皮细胞（角质形成细胞） 给诸如香烟烟雾和酒精之类的有害特工倾向于ESCC，却是恶性 即使响应这种压力源，单个食管角质形成细胞的转化也很少。那很重要 在正常食管角质形成细胞中必须存在细胞保护机制，以应对这些感染和 防止这些细胞的恶性转化。迄今为止，这些机制尚不清楚。这里， 我们建议描绘食管角质形成细胞中重要的细胞保护途径，重点关注钥匙 转录调节剂Krüppel样因子5（KLF5）和肿瘤抑制p53在反应中 生理压力。在正常的上皮中，KLF5的功能促进增殖和迁移并抑制 炎症，以及在新的初步数据中，我们在细胞中定义了KLF5和野生型p53的关键功能 对非转化的食管角质形成细胞中外源性应激的反应，并证明突变体 p53调节了KLF5的全基因组结合，从而改变了受KLF5在IN中的目标和途径 这个上下文。我们的总体假设是KLF5和p53是分子的变阻器，协调一致 调节食道鳞状上皮反应对外源应激源，并破坏 调节是有缺陷的细胞修复和ESCC的基础。为了检验这一假设，我们将追求以下 相互关联的特定目的：1。我们将在正常角质形成细胞中定义KLF5-P53目标和功能 外源应力； 2。我们将确定稳态中全基因组KLF5结合的突变p53改变 和压力； 3。我们将描述KLF5和P53在由食管粘膜损伤中的功能 吸烟和酒精。总体而言，拟议的研究提供了一个框架，以了解 哪种正常的食管角质形成细胞对环境应力及其扰动的反应 鳞状食管中恶性转化和进展的反应。