The role of Klf5 in GI epithelial homeostasis and disease

Klf5 在胃肠道上皮稳态和疾病中的作用

• 批准号: 7812268
• 负责人: JONATHAN P KATZ
• 金额: $ 31.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812268
• 关键词: Anoikis; Area; Award; Biological Assay; Breast; Cell Proliferation; Cells; Cyclin D1; Data; Diagnosis; Disease; Economics; Epidermal Growth Factor; Epithelial; Epithelial Cells; Esophageal; Esophageal Squamous Cell; Esophagus; Extracellular Matrix; Funding; Gene Mutation; Genes; Goals; Growth Factor Receptors; Homeostasis; Human; Immigration; Integrins; Intestines; Malignant - descriptor; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of prostate; Mediating; Mus; Mutation; Nude Mice; Occupations; Parents; Pennsylvania; Positioning Attribute; Protein p53; Protocols documentation; Regulation; Request for Proposals; Research; Research Personnel; Role; Schools; Signal Transduction; Skin; Stratum Basale; TP53 gene; Training; Transgenic Mice; Transgenic Organisms; Universities; Yang; carcinogenesis; cell transformation; cost; functional loss; gastrointestinal epithelium; in vivo; integrin-linked kinase; keratinocyte; medical schools; meetings; migration; novel strategies; parent grant; public health relevance; research study; tumorigenesis

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.

描述（由申请人提供）：宾夕法尼亚大学医学院对当地经济做出了巨大贡献。2008年，该校创造了37，000个就业机会和54亿美元的区域经济活动，该地区训练有素的劳动力为840个开放的宾夕法尼亚大学员工研究职位提供了24，600多份申请。目前的提议将涉及创造一个新的工作，一个专门为这次竞争性修订聘请的博士后研究员。该提案还将通过加快科学研究的克里思来实现ARRA的具体目标。Kruppel样因子5（KLF 5; IKLF; BTEB 2）是胃肠道上皮细胞增殖的关键调节因子。在食管中，Klf 5特异性地表达于增殖基底层，并且小鼠中Klf 5的转基因表达增加食管上皮增殖。然而，KLF 5抑制增殖，促进失巢凋亡，并减少食管鳞癌细胞的侵袭。此外，Klf 5在未转化的IEC-18和IMCE肠细胞中促进增殖并激活细胞周期蛋白D1，但在Ras介导的转化后抑制增殖并不能激活细胞周期蛋白D1。KLF 5在乳腺癌和前列腺癌中也被删除或下调。这些研究强调了KLF 5的背景依赖性作用。p53基因突变在食管鳞癌中很常见。然而，在小鼠和人类中很少看到p53缺失或p53突变的上皮癌。在初步的数据中，我们发现，功能性KLF 5和p53的组合，但不是单独的损失，足以转化人原代食管角质形成细胞。我们推测p53和KLF 5协同调节食管肿瘤的发生。此外，我们确定Notch 1，肿瘤抑制因子和p53在皮肤角质形成细胞的目标，作为KLF 5的转录靶点。因此，我们提出了以下具体目标：检查转化和协调调节的Notch 1基因在食管角质形成细胞KLF 5和p53。在建立在母体R 01的特定目标（“Klf 5在GI上皮稳态和疾病中的作用”）的同时，这种竞争性修订代表了受资助R 01的范围或研究方案的显著扩展。因此，本提案要求支付费用，以支持新的研究目标和目的，这些目标和目的超出了批准的母补助金的范围。总的来说，我们预计这些研究将确定KLF 5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世界上最致命的癌症之一。 公共卫生相关性：这一提议将导致创造一个新的工作，一个专门为这次竞争性修订聘请的博士后研究员。此外，本文提出的研究将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世界上最致命的癌症之一。