BIOCHEMISTRY OF BRAIN TUMOR MICROVESSEL DEVELOPMENT

脑肿瘤微血管发育的生物化学

• 批准号: 6348697
• 负责人: John J Laterra
• 金额: $ 5万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348697
• 关键词: SCID mouse; angiogenesis; animal genetic material tag; antisense nucleic acid; astrocytoma; blood brain barrier; capillary; cell migration; cell proliferation; gene induction /repression; growth factor receptors; hepatocyte growth factor; neoplasm /cancer genetics; neoplasm /cancer invasiveness; oncoproteins; protein structure function; tissue /cell culture; transfection; vascular endothelium; vascular endothelium permeability

DESCRIPTION (Applicants Abstract): Malignant gliomas are aggressive brain tumors with an increasing incidence. Their poor prognosis is due to the ability of glioma cells to proliferate rapidly, invade surrounding brain, induce angiogenesis, and disrupt blood-brain barrier (BBB) function. We have substantial evidence that the multifunctional cytokine and angiogenic factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor c-met in human gliomas and glioblastoma cells (ii) a correlation between glioma grade and SF/HGF content in clinical glioma specimens, (iii) SF/HGF induction of glioblastoma cell migration, and (iv) enhanced in vivo glioma growth and tumor-associated angiogenesis following SF/HGF gene transfer. This application proposes in vitro and in vivo experiments to determine how SF/HGF and c-met contribute to glioblastoma malignancy, and if inhibiting SF/HGF:c-met signaling can be used to reverse glioma malignancy, angiogenesis, and BBB dysfunction. Aim #1 will determine how purified and glioma cell-derived SF/HGF alters BBB function in vivo. The effects of SF/HGF on BBB permeability and endothelial cell expression of BBB-specific proteins will be quantified. Aims #2 and #3 will determine if inhibiting endogenous SF/HGF:c-met signaling by genetically altering glioblastoma cell lines reduces their malignancy in vitro and in vivo. Aim #2 will examine the effects of inhibiting glioblastoma cell SF/HGF expression/function using gene transfer of antisense SF/HGF and NK2, a naturally occurring SF/HGF receptor antagonist. Aim #3 will determine the effects of inhibiting c-met expression function by gene transfer of antisense c-met and dominant-negative mutant c-met receptors. The effects of these genetic manipulations on glioblastoma cell anchorage-dependent and - independent proliferation, migration , and invasion in vitro, and on tumor growth, angiogenesis, and BBB dysfunction in vivo will be quantified. Aim #4 will determine if tumor malignancy can be reversed in established SF/HGF-producing gliomas by using the most promising approaches of Aims #2 and #3 with adenoviral- and cell-based gene transfer. These studies will produce new information on mechanisms of glioblastoma malignancy and BBB dysfunction and will establish the feasibility of altering SF/HGF:c-met signaling within gliomas for therapeutic intervention.

描述(应聘者摘要)：恶性胶质瘤是一种侵袭性脑 肿瘤发病率呈上升趋势。他们预后不佳是由于 胶质瘤细胞快速增殖，侵袭周围大脑的能力， 诱导血管生成，破坏血脑屏障(BBB)功能。我们 有确凿证据表明多功能细胞因子和血管生成 因子分散因子/肝细胞生长因子及其受体 C-MET在人脑胶质瘤和胶质母细胞瘤细胞中的表达(II) 临床标本中胶质瘤分级和SF/HGF含量的研究 诱导胶质母细胞瘤细胞迁移，以及(Iv)增强体内胶质瘤 SF/HGF基因转移后的生长和肿瘤相关血管生成。 这项应用提出了体外和体内实验，以确定如何 SF/HGF和c-MET参与了胶质母细胞瘤的恶性进展，如果抑制 SF/HGF：C-MET信号可用于逆转胶质瘤的恶性， 血管生成和血脑屏障功能障碍。目标1将确定如何提纯和 胶质瘤细胞来源的SF/HGF在体内改变BBB功能。的影响 SF/HGF对BBB通透性及内皮细胞BBB特异性表达的影响 蛋白质将被量化。目标2和3将决定是否抑制 基因改变胶质母细胞瘤细胞的内源性SF/HGF：C-MET信号转导 LINES在体外和体内都能降低它们的恶性程度。Aim#2将检查 环磷酰胺对胶质母细胞瘤细胞SF/HGF表达/功能的抑制作用 反义SF/HGF和自然产生的SF/HGF NK2的基因转移 受体拮抗剂。目标#3将确定抑制c-met的效果 反义c-Met和反义c-Met基因转移的表达功能 显性负性突变的c-met受体。这些基因的影响 胶质母细胞瘤细胞锚定依赖性和非依赖性的调控 体外增殖、迁移和侵袭，以及对肿瘤生长的影响， 血管生成和体内的血脑屏障功能障碍将被量化。目标#4将 确定肿瘤的恶性程度是否可以逆转 使用AIMS#2最有希望的方法产生SF/HGF胶质瘤 第三种是基于腺病毒和细胞的基因转移。这些研究将 提供关于胶质母细胞瘤恶性和血脑屏障机制的新信息 并将确定改变SF/HGF：C-MET的可行性 在胶质瘤内发出信号以进行治疗干预。