Alpha-Catenin in Regulation of Tissue Homeostasis and Cancer

α-连环蛋白调节组织稳态和癌症

• 批准号: 9057992
• 负责人: VALERI VASIOUKHIN
• 金额: $ 43.68万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057992
• 关键词: Address; Adherens Junction; Adhesions; Affect; Architecture; Attention; Attenuated; Cadherins; Cancer Model; Carcinoma; Cell Adhesion Molecules; Cell physiology; Cell-Cell Adhesion; Cells; Complex; Contact Inhibition; Data; Defect; Development; Down-Regulation; E-Cadherin; Epithelial; Epithelial Cells; Event; Genetic; Growth; Health; Homeostasis; Human; Inhibition of Cell Proliferation; Knowledge; Laboratories; Maintenance; Malignant Neoplasms; Maps; Mediating; Mesenchymal; Methods; Molecular; Mus; Neoplasm Metastasis; Normal tissue morphology; Pathway interactions; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Play; Primary Neoplasm; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skin; Small Interfering RNA; Squamous cell carcinoma; Stem cells; Structure; Technology; Testing; Therapeutic Intervention; Tissues; Transcription Coactivator; Transcriptional Activation; Tumor Suppression; Tumor Suppressor Proteins; Tyrosine Phosphorylation; alpha catenin; base; cancer stem cell; gain of function; in vivo; keratinocyte; knockout gene; loss of function; novel; novel therapeutic intervention; protein complex; research study; self-renewal; skin squamous cell carcinoma; src-Family Kinases; stem cell differentiation; tumor; tumor initiation

DESCRIPTION (provided by applicant): The ability to adhere to each other is one of the most fundamental cellular functions necessary for the formation of all metazoans. The most significant histological manifestation of epithelial tumor is the focal loss of normal tissue architecture. Maintenance of normal tissue organization is one of the primary functions of cell-cell adhesion structures and intercellular adhesion is often abnormal in epithelial cancer. Our laboratory is concentrating on understanding the normal and pathological function of cell-cell adhesion protein alphaE(epithelial)-catenin. AlphaE-catenin is often downregulated in a variety of human epithelial tumors: however, the significance of this downregulation and overall mechanisms of alpha-catenin in tissue homeostasis and cancer is not well understood. To understand the significance of alpha-catenin downregulation in human cancer, we model these events in mice using conditional gene knockout technology. These and other approaches resulted in realization that alpha-catenin plays an important role in regulation of self-renewal an differentiation of stem cells and the genetic loss of alpha-catenin in stem cell compartment can result in prominent defects in tissue homeostasis and development of cancer. In this proposal we will study the molecular mechanisms of alpha-catenin in signal transduction and use genetic loss-of-function and pharmacological inhibition experiments to explore the novel therapeutic interventions for the treatment of epithelial tumors displaying a decrease or loss of alpha-catenin expression.

描述（由申请人提供）：相互粘附的能力是所有后生动物形成所必需的最基本的细胞功能之一。上皮性肿瘤最显著的组织学表现是正常组织结构的局灶性丧失。维持正常组织结构是细胞-细胞粘附结构的主要功能之一，并且细胞间粘附在上皮癌中通常是异常的。我们的实验室致力于了解细胞间粘附蛋白α E（上皮）-连环蛋白的正常和病理功能。α E-连环蛋白通常在多种人类上皮肿瘤中下调：然而，这种下调的意义和α-连环蛋白在组织稳态和癌症中的总体机制尚未得到很好的理解。为了了解α-连环蛋白下调在人类癌症中的意义，我们使用条件性基因敲除技术在小鼠中模拟这些事件。这些和其他方法导致认识到α-连环蛋白在调节干细胞的自我更新和分化中起重要作用，并且干细胞区室中α-连环蛋白的遗传缺失可导致组织稳态的显著缺陷和癌症的发展。本研究拟通过研究α-catenin在信号转导中的分子机制，并利用基因功能丧失和药理学抑制实验，探索治疗α-catenin减少或缺失的上皮性肿瘤的新的治疗干预措施 表情