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Cytoprotective pathways in esophageal squamous epithelia

食管鳞状上皮的细胞保护途径

基本信息

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
项目类别：
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

项目摘要

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.

项目概要食道疾病是美国乃至全世界的重大健康问题，食管癌，其中80%以上是食管鳞状细胞癌（ESCC），位居第六位。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）吸烟和酒精等有害物质易患食管鳞癌，但仍呈恶性即使对这种应激源作出反应，单个食管角质形成细胞的转化也是罕见的。因此，重要的正常食管角质形成细胞中必须存在细胞保护机制来应对这些损伤和防止这些细胞的恶变。迄今为止，这些机制尚未得到很好的理解。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，重点关注关键转录调节因子 Krüppel 样因子 5 (KLF5) 和肿瘤抑制因子 p53 在响应中生理压力。在正常上皮细胞中，KLF5 的功能是促进增殖和迁移并抑制炎症，并且在新的初步数据中，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管角质形成细胞对外源应激的反应，并证明突变体 p53 调节 KLF5 的全基因组结合，从而改变 KLF5 控制的靶标和途径这个背景。我们的首要假设是 KLF5 和 p53 是一个分子变阻器，协同作用调节食管鳞状上皮对外源性应激源的反应，并且破坏这种反应调节是有缺陷的细胞修复和食管鳞癌的基础。为了检验这个假设，我们将进行以下研究相互关联的具体目标： 1. 我们将定义正常角质形成细胞中的 KLF5-p53 靶标和功能外源性压力； 2. 我们将确定全基因组 KLF5 结合在稳态中的突变 p53 改变和压力； 3. 我们将阐述KLF5和p53在食管粘膜损伤中的功能吸烟和饮酒。总的来说，拟议的研究提供了一个框架来理解这些机制正常食管角质形成细胞对环境压力及其扰动做出反应鳞状食管恶性转化和进展的基础反应。