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）的数十亿个神经元和胶质细胞中，有一个丰富的细胞外基质（ECM）蛋白环境。大多数中枢神经系统细胞通过细胞表面粘附受体的整合素家族成员与ECM成分相互作用。整合素- ecm通讯的精确调控是正常中枢神经系统发育和稳态所必需的，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病。在这个项目中，我们将确定av¿8整合素如何参与致命的脑癌，多形性胶质母细胞瘤（GBM）的发病机制。GBMs和其他高级别胶质瘤发生严重的血管病变，包括异常的血管生成和相关的水肿和出血。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降低有助于高级别胶质瘤的血管病变。开展这些研究的基本原理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，这是胶质瘤的推定起源细胞；（ii）基因消融小鼠神经干细胞和星形胶质细胞中的小鼠av或¿8整合素基因导致脑特异性血管表型，类似于在高级别胶质瘤中观察到的病理；（iii）缺乏av¿8整合素的转化星形胶质细胞产生颅内肿瘤，其血管异常与高级别胶质瘤相似；（iv）肿瘤干细胞主要导致胶质瘤的血管病变，而av¿8整合素的表达定义了人类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。本项目拟通过实验研究av - 8整合素在脑胶质瘤形成过程中在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学工具，包括av和¿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av¿8整合素在切除的人类胶质瘤组织和人类胶质瘤干细胞中的表达和功能。我们提出以下具体目标：(1)我们将利用原位和基因工程小鼠胶质瘤模型确定av¿8整合素在肿瘤诱导的血管生成中的功能作用；(2)我们将确定av¿8整合素在人类恶性胶质瘤血管病变中的功能作用。总的来说，这些实验将阐明av¿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变有关。这项工作可能最终导致治疗或预防人类高级胶质瘤进展的新治疗策略。公共卫生相关性：在美国，神经胶质瘤每年折磨着大约2万人。它们代表了最常见的原发性脑肿瘤类型，在晚期，它们是最致命的癌症之一。了解导致胶质瘤生长、血管生成和侵袭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疾病的发病机制。在这个项目中，我们将研究细胞粘附分子，被称为整合素，如何调节小鼠和人类胶质瘤的发生和进展。这些结果可能确定新的治疗靶点，以治疗或预防人类胶质瘤的发展。

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.