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重大贡献。 2008年，该学院创造了37,000个就业岗位，为地区经济活动创造了54亿美元的收入，该地区训练有素的劳动力为宾夕法尼亚大学840个开放的研究职位提出了24,600多份申请。目前的提案将涉及创建一个新职位，即专门为此竞争性修订聘请的一名博士后研究员。该提案还将通过加快科学研究的节奏来实现 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在增殖基底层特异性表达，并且Klf5在小鼠体内的转基因表达增加了食管上皮增殖。然而，KLF5 抑制增殖、促进失巢凋亡并减少食管鳞状癌细胞的侵袭。此外，Klf5 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且无法激活细胞周期蛋白 D1。 KLF5 在乳腺癌和前列腺癌中也被删除或下调。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，在 p53 缺失或仅 p53 突变的小鼠和人类中很少见上皮癌。在初步数据中，我们表明，功能性 KLF5 和 p53 的联合（而非单独）丧失足以转化人原代食管角质形成细胞。我们假设 p53 和 KLF5 协调调节食管肿瘤发生。此外，我们还确定了 Notch1（一种肿瘤抑制因子和皮肤角质形成细胞中的 p53 靶标）作为 KLF5 的转录靶标。因此，我们提出以下具体目标：检查KLF5和p53对食管角质形成细胞中Notch1基因的转化和协调调节。在母体 R01 的具体目标（“Klf5 在胃肠道上皮稳态和疾病中的作用”）的基础上，这一竞争性修订代表了受资助的 R01 的范围或研究方案的显着扩展。因此，该提案要求支付费用来支持超出批准的母基金范围的新研究目标和目标。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（美国和全世界最致命的癌症之一）的诊断和治疗提供新方法。 公共卫生相关性：该提案将导致创造一个新的工作岗位，即专门为此竞争性修订聘用的一名博士后研究员。此外，这里提出的研究将为食管鳞状细胞癌的诊断和治疗提供新方法，食管鳞状细胞癌是美国和全世界最致命的癌症之一。