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: 8643463
• 负责人: VALERI VASIOUKHIN
• 金额: $ 43.55万
• 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/8643463
• 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; 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; 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; public health relevance; 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)：相互粘连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。维持正常的组织结构是细胞间黏附结构的主要功能之一，而细胞间黏附在上皮性肿瘤中往往是异常的。本实验室致力于了解细胞-细胞黏附蛋白αE(上皮)-连环蛋白的正常和病理功能。α-连环蛋白在多种人类上皮性肿瘤中经常下调：然而，这种下调的意义以及α-连环蛋白在组织动态平衡和癌症中的整体机制还不是很清楚。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身上对这些事件进行了建模。这些方法和其他方法使人们认识到α-连环蛋白在自我更新和干细胞分化的调节中起着重要作用，而干细胞间的α-连环蛋白基因缺失可能导致组织内稳态的显着缺陷和癌症的发展。在这个方案中，我们将研究α-连环蛋白在信号转导中的分子机制，并利用遗传功能丧失和药物抑制实验来探索治疗表现为α-连环蛋白减少或丢失的上皮性肿瘤的新的治疗干预措施。 表情。