Regulation of esophageal gene expression and function by KLF5 and p53

描述（由申请人提供）：食管衬里经常暴露于刺激物，如酒精、香烟烟雾、热饮、膳食亚硝基化合物和胃十二指肠内容物的回流物，食管疾病是美国和全世界的重大健康问题。 例如，胃食管反流病（GERD）每年导致890万美国诊所就诊，并且食管癌是全世界癌症死亡的第六大最常见原因。 在食管上皮中，关键的转录调节因子KLF 5（KLF 5）促进正常的增殖和迁移，正如我们所展示的那样，我们最近在食管上皮细胞中发现了KLF 5和p53之间的新关系，其中p53作为KLF 5的“分子开关”。 原代人食管角化细胞中的p53突变将KLF 5从促增殖转化为抗增殖，这种作用主要由p21 Waf 1/Cip 1介导，并且当p53突变而不是野生型p53时，KLF 5转录激活角化细胞肿瘤抑制因子NOTCH 1。 在额外的初步数据中，我们证明了KLF 5抑制食管角化细胞中的p53，并为KLF 5和p53的全基因组协调调节提供了证据。 我们的总体假设是，KLF 5和p53编排了一个广泛的转录程序在食管角化细胞，控制增殖，生长停滞，凋亡和转化。 为了验证这一假设，我们将追求以下相互关联的具体目标：1。我们将描绘出 KLF 5调节p53水平和功能的机制~ 2.我们将定义KLF 5在p21 Waf 1/Cip 1 ~ 3上功能转换的机制。我们将在野生型和突变型p53和4的背景下确定KLF 5的共同和排他性靶点。我们将在体内确定KLF 5缺失和p53突变的功能后果。 这些补充方法得到了我们已发表和未发表的强大初步数据的支持。 此外，PI是一位经验丰富的研究者，他是Kréppel样因子（KLF），转录调控，胃肠道疾病动物模型和食管鳞状细胞生物学的专家，正如最近在Cancer Research，PLoS One，Cell Cycle和Neoplasia中的相关通讯作者出版物所证明的那样。 此外，PI还得到了一流的研究团队的支持，并得到了专家合作者的补充，以及宾夕法尼亚大学和NIH资助的消化和肝脏疾病分子研究中心的卓越资源，设施和智力环境。 总的来说，拟议的研究将提供关键的见解食管上皮稳态的转录调控和食管疾病，良性和恶性的分子途径。

DESCRIPTION (provided by applicant): The esophageal lining is regularly exposed to irritants such as alcohol, cigarette smoke, hot beverages, dietary nitroso-compounds, and refluxate of gastro-duodenal contents, and disorders of the esophagus are significant health problems in the U.S. and throughout the world. For example, gastroesophageal reflux disease (GERD) leads to 8.9 million U.S. clinic visits annually, and esophageal cancer is the 6th most common cause of cancer death worldwide. In esophageal epithelia, the key transcriptional regulator Kr�ppel-like factor 5 (KLF5) promotes normal proliferation and migration, as we have shown, and we recently identified a novel relationship between KLF5 and p53 in esophageal epithelial cells, whereby p53 acts as a "molecular switch" for KLF5. p53 mutation in primary human esophageal keratinocytes converts KLF5 from pro-proliferative to anti-proliferative, an effect mediated predominantly by p21Waf1/Cip1, and KLF5 transcriptionally activates the keratinocyte tumor suppressor NOTCH1 when p53 is mutant but not with wild-type p53. In additional Preliminary Data, we demonstrate that KLF5 suppresses p53 in esophageal keratinocytes and provide evidence for genome-wide coordinate regulation by KLF5 and p53. Our overarching hypothesis is that KLF5 and p53 orchestrate a broad transcriptional program in esophageal keratinocytes that controls proliferation, growth arrest, apoptosis, and transformation. To test this hypothesis, we will pursue the following interrelated Specific Aims: 1. We will delineate the mechanisms through which KLF5 regulates p53 levels and function~ 2. We will define the mechanism for KLF5 functional switching on p21Waf1/Cip1~ 3. We will identify common and exclusive targets of KLF5 in the context of wild-type and mutant p53~ and 4. We will determine the functional consequences of KLF5 loss and p53 mutation in vivo. These complementary approaches are supported by our robust Preliminary Data, both published and unpublished. Moreover, the PI is an experienced investigator who is an expert in the Kr�ppel-like factors (KLFs), transcriptional regulation, animal models of gastrointestinal diseases, and esophageal squamous cell biology, as demonstrated by recent, relevant corresponding-author publications in Cancer Research, PLoS One, Cell Cycle, and Neoplasia. In addition, the PI is supported by a superb research team, complemented by expert collaborators, and by the exceptional resources, facilities, and intellectual environment of the University of Pennsylvania and the NIH-funded Center for Molecular Studies in Digestive and Liver Diseases. Overall, the proposed studies will provide key insights into the transcriptional regulation of esophageal epithelial homeostasis and the molecular pathways that underlie esophageal diseases, both benign and malignant.