Analysis of alphaVbeta8 Integrin In Gliomagenesis

描述（由申请人提供）：在脊椎动物中枢神经系统（CNS）中的数十亿神经元和神经胶质中存在丰富的细胞外基质（ECM）蛋白环境。 大多数CNS细胞通过细胞表面粘附受体的整合素家族成员与ECM组分相互作用。 整合素-ECM通讯的精确调节对于正常CNS发育和稳态是必需的，并且这些事件的异常调节可促成各种CNS疾病（包括癌症）的发病机制。 在这个项目中，我们将确定α v β 8整合素如何有助于致命的脑癌，多形性胶质母细胞瘤（GBM）的发病机制。 GBM和其他高级别神经胶质瘤发展为严重的血管病变，包括异常血管生成和相关的水肿和出血。 我们的工作假设是，在高级别胶质瘤中，肿瘤起始细胞中整合素α v β 8的表达和功能降低导致血管病变。 进行这些研究的基本原理是基于以下实验数据：（i）α v β 8整联蛋白在神经干细胞和星形胶质细胞中表达，这是神经胶质瘤的假定起源细胞;（ii）在小鼠神经干细胞和星形胶质细胞中遗传切除小鼠α v或β 8整联蛋白基因导致脑特异性血管表型，其与在高级别神经胶质瘤中观察到的病理学相似;（iii）缺乏α v β 8整联蛋白的转化的星形胶质细胞产生具有与在高级别胶质瘤中发现的血管异常相似的血管异常的颅内肿瘤;和（iv）肿瘤干细胞主要促成胶质瘤中的血管病理，并且α v β 8整联蛋白表达限定了人胶质瘤干细胞的亚群，其中近50%的GBM干细胞缺乏α v β 8整联蛋白表达。 在这个项目中，我们提出了实验来研究神经胶质瘤形成过程中，α v β 8整合素在脑肿瘤起始细胞中的功能。 为了实现这些目标，我们将使用一套独特的分子遗传工具，包括α v和β 8整合素突变小鼠，以及从突变动物中纯化的细胞。 此外，我们将研究α v <$8整合素在切除的人脑胶质瘤组织和人脑胶质瘤干细胞中的表达和功能。 我们提出了以下具体目标：（1）我们将确定α v <$8整合素在肿瘤诱导的血管生成中的功能作用，使用原位和基因工程小鼠胶质瘤模型，和（2）我们将确定α v <$8整合素在血管病理学中的功能作用，这些病理学是人类恶性胶质瘤的典型。 总的来说，这些实验将阐明α v β 8整合素在胶质瘤形成过程中的功能作用，特别是与肿瘤诱导的血管病理学相关的功能作用。 这项工作可能最终导致新的治疗策略，用于治疗或预防人类高级别胶质瘤的进展。 公共卫生相关性：胶质瘤每年在美国折磨大约20，000人。 它们代表了最常见的原发性脑肿瘤类型，并且在其晚期阶段，它们是最致命的癌症形式之一。 了解有助于胶质瘤生长、血管生成和侵袭性的基本细胞和分子事件可能导致新的治疗策略来治疗或预防这种隐匿性疾病的发病机制。 在这个项目中，我们将研究细胞粘附分子，称为整合素，如何调节小鼠和人类胶质瘤的发生和发展。 这些结果可能会发现新的治疗靶点，以治疗或预防人类神经胶质瘤的发展。

DESCRIPTION (provided by applicant): Among the billions of neurons and glia in the vertebrate central nervous system (CNS) is a rich milieu of extracellular matrix (ECM) proteins. Most CNS cells interact with ECM components via members of the integrin family of cell surface adhesion receptors. Precise regulation of integrin-ECM communication is necessary for normal CNS development and homeostasis, and abnormal regulation of these events can contribute to the pathogenesis of various CNS diseases, including cancer. In this project we will determine how av¿8 integrin contributes to the pathogenesis of the deadly brain cancer, glioblastoma multiforme (GBM). GBMs and other high-grade gliomas develop severe blood vessel pathologies, including abnormal angiogenesis and associated edema and hemorrhage. Our working hypothesis is that reduced av¿8 integrin expression and function in tumor-initiating cells contributes to vascular pathologies in high-grade gliomas. The rationale for pursuing these studies is based on the following experimental data: (i) av¿8 integrin is expressed in neural stem cells and astroglia, which are presumptive cells of origin for glioma; (ii) genetic ablation of the murine av or ¿8 integrin genes in mouse neural stem cells and astroglia results in brain-specific vascular phenotypes that are similar to pathologies observed in high-grade gliomas; (iii) transformed astroglia that lack av¿8 integrin generate intracranial tumors with vascular abnormalities similar to those found in high-grade gliomas; and (iv) tumor stem cells primarily contribute to vascular pathologies in gliomas, and av¿8 integrin expression defines sub-populations of human glioma stem cells, with nearly 50% of GBM stem cells lacking av¿8 integrin expression. In this project we propose experiments to study functions for av¿8 integrin in brain tumor-initiating cells during gliomagenesis. To accomplish these goals we will use a unique set of molecular genetic tools, consisting of av and ¿8 integrin mutant mice, as well as cells purified from mutant animals. Additionally, we will study the expression and function of av¿8 integrin in resected human glioma tissues and human glioma stem cells. We propose the following Specific Aims: (1) We will determine the functional roles for av¿8 integrin in tumor-induced angiogenesis using orthotopic and genetically engineered mouse models of glioma, and (2) We will determine the functional roles for av¿8 integrin in vascular pathologies that typify human malignant gliomas. Collectively, these experiments will elucidate the functional role for av¿8 integrin during gliomagenesis, particularly related to tumor-induced vascular pathologies. This work may eventually lead to new therapeutic strategies for treating or preventing the progression of high-grade gliomas in humans. PUBLIC HEALTH RELEVANCE: Gliomas afflict approximately 20,000 people within the United States each year. They represent the most common type of primary brain tumors, and, in their advanced stages, they are one of the deadliest forms of cancer. Understanding the basic cellular and molecular events that contribute to glioma growth, angiogenesis, and invasiveness may lead to new therapeutic strategies to treat or prevent the pathogenesis of this insidious disease. In this project we will study how cell adhesion molecules, known as integrins, regulate the onset and progression of gliomas in mice and humans. These results may identify new therapeutic targets to treat or prevent the development of gliomas in humans.