Alpha-Catenin in Regulation of Tissue Homeostasis and Cancer

α-连环蛋白调节组织稳态和癌症

基本信息

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
项目类别：
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

项目摘要

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）：彼此粘附的能力是形成所有后生动物所必需的最基本的细胞功能之一。上皮肿瘤最重要的组织学表现是正常组织结构的局灶性丧失。正常组织组织的维持是细胞 - 细胞粘附结构的主要功能之一，细胞间粘附在上皮癌中通常异常。我们的实验室集中于了解细胞 - 细胞粘附蛋白α（上皮）-Catenin的正常和病理功能。在各种人的上皮肿瘤中，α-钙蛋白通常被下调：但是，这种下调和α-钙蛋白在组织稳态和癌症中的下调和总体机制的重要性尚不清楚。为了了解α-catenin下调在人类癌症中的重要性，我们使用条件基因敲除技术在小鼠中对这些事件进行建模。这些方法和其他方法导致人们意识到，α-钙蛋白在调节自我更新的干细胞分化中起着重要作用，而干细胞区室中α-钙蛋白的遗传丧失会导致组织伴有组织膜的显着缺陷和癌症的发育。在该提案中，我们将研究信号转导中α-catenin的分子机制，并使用遗传丧失功能和药理学抑制实验，以探索新的治疗性干预措施，用于治疗上皮肿瘤，显示出降低或损失alpha-catenin 表达。