Analysis of alphaVbeta8 Integrin In Gliomagenesis

描述(申请人提供)：在脊椎动物中枢神经系统(CNS)的数十亿个神经元和胶质细胞中，有丰富的细胞外基质(ECM)蛋白质环境。大多数中枢神经系统细胞通过细胞表面黏附受体整合素家族成员与细胞外基质成分相互作用。对整合素-ECM通讯的精确调控对于中枢神经系统的正常发育和内稳态是必要的，而这些事件的异常调控可能导致包括癌症在内的各种中枢神经系统疾病的发生。在这个项目中，我们将确定av？8整合素如何在致命性脑癌--多形性胶质母细胞瘤(GBM)的发病机制中发挥作用。胶质瘤和其他高级别胶质瘤发展成严重的血管病理，包括异常的血管生成以及相关的水肿和出血。我们的工作假设是，肿瘤启动细胞中av？8整合素表达和功能的减少与高级别胶质瘤的血管病理有关。进行这些研究的理由是基于以下实验数据：(I)av？8整合素在神经干细胞和星形胶质细胞中表达，这两种细胞可能是胶质瘤的起源细胞；(Ii)小鼠神经干细胞和星形胶质细胞中的小鼠av或整合素基因的遗传消融导致与高级别胶质瘤中观察到的病理相似的脑特异性血管表型；(Iii)缺乏av？8整合素的转化星形胶质细胞产生的颅内肿瘤具有与高级别胶质瘤相似的血管异常；肿瘤干细胞在胶质瘤的血管病理中起主要作用，av？8整合素的表达定义了人脑胶质瘤干细胞的亚群，近50%的GBM干细胞缺乏av？8整合素的表达。在这个项目中，我们提出了实验来研究av？8整合素在脑肿瘤启动细胞中在胶质瘤形成过程中的作用。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av和？8整合素突变小鼠，以及从突变动物中提纯的细胞。此外，我们还将研究av？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)我们将利用原位和基因工程的小鼠胶质瘤模型来确定av？8整合素在肿瘤诱导的血管生成中的功能作用，以及(2)我们将确定av？8整合素在典型的人类恶性胶质瘤血管病理中的功能作用。总而言之，这些实验将阐明av？8整合素在胶质瘤形成中的功能作用，特别是与肿瘤诱导的血管病理相关的作用。这项工作可能最终导致新的治疗策略来治疗或防止人类高级别胶质瘤的进展。与公共健康相关：美国每年约有2万人患上神经胶质瘤。它们代表了最常见的原发脑瘤类型，在晚期，它们是最致命的癌症之一。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会导致新的治疗策略来治疗或预防这种潜伏性疾病的发病机制。在这个项目中，我们将研究被称为整合素的细胞黏附分子如何调控小鼠和人类胶质瘤的发生和发展。这些结果可能会确定新的治疗靶点，以治疗或防止人类胶质瘤的发展。

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.