The Roles of Osteonectin and Osteoactivin in Gliomas

骨连接素和骨激活素在神经胶质瘤中的作用

• 批准号: 6709943
• 负责人: JEREMY N RICH
• 金额: $ 16.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709943
• 关键词: RNA interference; Retroviridae; animal tissue; disease /disorder model; gene induction /repression; glioma; inhibitor /antagonist; laboratory mouse; matrigel; membrane proteins; metastasis; neoplasm /cancer invasiveness; neutralizing antibody; osteonectin; pathologic process; small molecule; tissue /cell preparation; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): The primary goal of this project is to test the hypothesis that two bone-related genes - osteonectin, which is a secreted extracellular matrix protein over-expressed in a wide range of advanced human cancers, and osteoactivin, which is a structurally unrelated transmembrane protein also over-expressed in several cancers - play important roles in the pathological process of glioma invasion. Although many of the genetic alterations that dysregulate the cell processes of growth and death involved in tumor initiation have been elucidated in recent years, less progress has been made in the complex but critical processes of tumor invasion, metastasis, and angiogenesis. Invasion is particularly important in the pathophysiology of gliomas as tumor cell infiltration of normal brain prevents curative resection. With this emphasis, our preliminary results suggest that osteonectin and osteoactivin can mediate critical tumor cell behaviors. We have shown that the expression of osteonectin and osteoactivin can induce spontaneous metastases and tumor cell invasion into the brain along penetrating blood vessels. Hypothesis: We hypothesize that osteonectin and osteoactivin expression can induce glioma invasion through the modification of tumor microenvironment, and that these mechanisms can be targeted to inhibit glioma invasion. To firmly establish the role of osteonectin and osteoactivin in the pathophysiology of gliomas and elucidate the mechanism by which osteonectin and osteoactivin functions to lay the foundation for the development of novel therapeutics directed towards osteonectin and osteoactivin, we will focus our studies on the following two Specific Aims: 1) Define the contributions of osteonectin and osteoactivin to the invasive phenotype of glioma. 2) Validate osteonectin and osteoactivin as potential therapeutic targets in glioma invasion. It is hoped that these studies will provide the basis of novel therapeutic interventions for patients with malignant gliomas.

描述（由申请人提供）：本项目的主要目标是检验两种骨相关基因-骨粘连蛋白（一种在多种晚期人类癌症中过度表达的分泌性细胞外基质蛋白）和骨激活素（一种在多种癌症中过度表达的结构无关的跨膜蛋白）-在胶质瘤侵袭的病理过程中发挥重要作用的假设。尽管近年来已经阐明了许多参与肿瘤起始的细胞生长和死亡过程失调的遗传改变，但在肿瘤侵袭、转移和血管生成的复杂但关键的过程中取得的进展较少。侵袭在神经胶质瘤的病理生理学中是特别重要的，因为正常脑的肿瘤细胞浸润阻止了治愈性切除。有了这个重点，我们的初步结果表明，骨粘连蛋白和骨激活素可以介导关键的肿瘤细胞行为。我们已经表明，骨连接素和骨激活素的表达可以诱导自发转移和肿瘤细胞沿沿着穿透血管侵入脑。 假设：我们推测骨连接素和骨激活素的表达可以通过改变肿瘤微环境来诱导胶质瘤的侵袭，并且这些机制可以靶向抑制胶质瘤的侵袭。为了牢固确立骨连接素和骨激活素在神经胶质瘤病理生理学中的作用，并阐明骨连接素和骨激活素发挥作用的机制，为开发针对骨连接素和骨激活素的新型疗法奠定基础，我们将重点研究以下两个特定目标： 1)明确骨粘连蛋白和骨激活素对胶质瘤侵袭表型的作用。2)骨粘连蛋白和骨激活素作为胶质瘤侵袭的潜在治疗靶点。 希望这些研究能为恶性胶质瘤患者提供新的治疗干预措施的基础。