The role of Klf5 in GI epithelial homeostasis and disease

描述（由申请人提供）：宾夕法尼亚大学医学院为当地经济做出了重大贡献。2008年，该学院为该地区创造了37,000个就业岗位和54亿美元的经济活动，该地区训练有素的劳动力为840个宾夕法尼亚大学的研究职位提供了超过24,600份申请。目前的提议将包括设立一个新职位，即专门为这一竞争性修订而聘用的博士后研究员。该提案还将通过加快科学研究的节奏来满足ARRA的具体目标。kruppel样因子5 （KLF5； IKLF; BTEB2）是胃肠道上皮细胞增殖的关键调节因子。在食管中，Klf5在增生性基底层特异性表达，转基因Klf5在小鼠体内的表达增加了食管上皮的增殖。然而，KLF5可以抑制食管鳞癌细胞的增殖，促进癌变，减少其侵袭。此外，在未转化的IEC-18和IMCE肠细胞中，Klf5促进增殖并激活cyclin D1，但在ras介导的转化后，Klf5抑制增殖并不能激活cyclin D1。KLF5在乳腺癌和前列腺癌中也缺失或下调。这些研究强调了KLF5的环境依赖性作用。P53基因突变在食管鳞癌中很常见。然而上皮癌在小鼠和人类中很少发现p53缺失或p53突变。在初步数据中，我们发现功能性KLF5和p53的联合缺失，而不是单独缺失，足以转化人原发性食管角化细胞。我们假设p53和KLF5协同调节食道肿瘤的发生。此外，我们发现皮肤角质形成细胞中的肿瘤抑制因子和p53靶点Notch1是KLF5的转录靶点。因此，我们提出以下具体目的：研究KLF5和p53对食管角化细胞Notch1基因的转化和协调调控。虽然建立在亲本R01的特定目标（“Klf5在胃肠道上皮稳态和疾病中的作用”）之上，但这一竞争性修订代表了资助R01的范围或研究方案的重大扩展。因此，本提案要求费用用于支持已批准的父母资助范围之外的新研究目标和目的。总的来说，我们预计这些研究将确定KLF5在食管恶性转化中的关键作用，并为食管鳞状细胞癌的诊断和治疗提供新的方法，食管鳞状细胞癌是美国和全世界最致命的癌症之一。

DESCRIPTION (provided by applicant): The University of Pennsylvania School of Medicine contributes substantially to the local economy. In 2008, the School created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will involve the creation of one new job, a postdoctoral researcher hired specifically for this competitive revision. This proposal will also meet the specific goals of the ARRA by accelerating the tempo of scientific research. Kruppel-like factor 5 (KLF5; IKLF; BTEB2) is a key regulator of proliferation in gastrointestinal epithelia. In the esophagus, Klf5 is expressed specifically in the proliferative basal layer, and transgenic expression of Klf5 in mice increases esophageal epithelial proliferation. Yet, KLF5 inhibits proliferation, promotes anoikis, and decreases invasion of esophageal squamous cancer cells. Moreover, Klf5 promotes proliferation and activates cyclin D1 in non-tranformed IEC-18 and IMCE intestinal cells but inhibits proliferation and fails to activate cyclin D1 following Ras-mediated transformation. KLF5 is also deleted or down-regulated in breast and prostate cancers. These studies highlight a context dependent role for KLF5. p53 gene mutations are common in esophageal squamous cancers. Yet epithelial cancers are rarely seen in mice and humans with loss of p53 or p53 mutation alone. In preliminary data, we show that loss of functional KLF5 and p53 in combination, but not individually, is sufficient to transform human primary esophageal keratinocytes. We hypothesize that p53 and KLF5 coordinately regulate esophageal tumorigenesis. Moreover, we identify Notch1, a tumor suppressor and p53 target in skin keratinocytes, as a transcriptional target of KLF5. Thus, we propose the following Specific Aim: to examine transformation and the coordinate regulation of the Notch1 gene in esophageal keratinocytes by KLF5 and p53. While building upon the Specific Aims of the parent R01 ("The role of Klf5 in GI epithelial homeostasis and disease"), this competitive revision represents a significant expansion of the scope or research protocol of the funded R01. As such, this proposal requests costs to support new research objectives and aims that are outside of the scope of the approved parent grant. Overall, we anticipate that these studies will define a key role for KLF5 in malignant transformation in the esophagus and provide new approaches to the diagnosis and treatment of esophageal squamous cell cancer, one of the deadliest cancers in the U.S. and throughout the world. PUBLIC HEALTH RELEVANCE: This proposal will result in the creation of one new job, a postdoctoral researcher hired specifically for this competitive revision. Moreover, the studies proposed here will provide new approaches to the diagnosis and treatment of esophageal squamous cell cancer, one of the deadliest cancers in the U.S. and throughout the world.