BIOCHEMISTRY OF BRAIN TUMOR MICROVESSEL DEVELOPMENT

脑肿瘤微血管发育的生物化学

• 批准号: 6151561
• 负责人: John J Laterra
• 金额: $ 31.43万
• 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/6151561
• 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（申请人摘要）：恶性神经胶质瘤是侵袭性脑胶质瘤。 肿瘤的发病率越来越高。 他们的预后不佳是由于 神经胶质瘤细胞快速增殖，侵入周围脑组织， 诱导血管生成和破坏血脑屏障（BBB）功能。 我们 有充分的证据表明，多功能细胞因子和血管生成 SF/HGF及其受体 人胶质瘤和胶质母细胞瘤细胞中的c-met（ii） 临床胶质瘤标本中胶质瘤分级和SF/HGF含量，（iii）SF/HGF 诱导胶质母细胞瘤细胞迁移，和（iv）增强体内胶质瘤 SF/HGF基因转移后的生长和肿瘤相关的血管生成。 本申请提出了体外和体内实验，以确定如何 SF/HGF和c-met有助于恶性胶质母细胞瘤，并且如果抑制 SF/HGF：c-met信号传导可用于逆转胶质瘤恶性， 血管生成和BBB功能障碍。 目标#1将确定如何纯化和 胶质瘤细胞衍生的SF/HGF改变体内BBB功能。 的影响 SF/HGF对血脑屏障通透性和内皮细胞表达血脑屏障特异性 蛋白质将被量化。 目标#2和#3将决定是否抑制 内源性SF/HGF：通过基因改变胶质母细胞瘤细胞的c-met信号传导 lines在体外和体内降低了它们的恶性度。 目标#2将检查 抑制胶质母细胞瘤细胞SF/HGF表达/功能的作用 反义SF/HGF和天然存在的SF/HGF-NK 2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基因转移的表达功能， 显性失活突变型c-met受体。 这些基因的影响 对胶质母细胞瘤细胞贴壁依赖性和非贴壁依赖性的操作 体外增殖、迁移和侵袭，以及对肿瘤生长的影响， 将定量体内的血管生成和BBB功能障碍。 目标#4 确定肿瘤恶性程度是否可以逆转， 通过使用目标#2的最有希望的方法来产生SF/HGF的胶质瘤 和#3与腺病毒和细胞为基础的基因转移。 这些研究将 为恶性胶质母细胞瘤和血脑屏障的机制提供新的信息 功能障碍，并将建立改变SF/HGF的可行性：c-met 神经胶质瘤内的信号传导用于治疗干预。