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: 6895495
• 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/6895495
• 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(申请人提供)：这个项目的主要目标是验证两个与骨相关的基因在胶质瘤侵袭的病理过程中发挥重要作用的假说。骨连接蛋白是一种分泌型细胞外基质蛋白，在多种晚期人类癌症中过度表达，而骨活化素是一种结构无关的跨膜蛋白，也在几种癌症中过度表达。尽管近年来许多涉及肿瘤发生的细胞生长和死亡过程的基因改变已被阐明，但在肿瘤侵袭、转移和血管生成等复杂而关键的过程中取得的进展较少。侵袭性在脑胶质瘤的病理生理学中尤为重要，因为正常脑组织中的肿瘤细胞浸润阻碍了根治性切除。有了这个重点，我们的初步结果表明，骨连蛋白和骨活化素可以介导关键的肿瘤细胞行为。我们已经证明，骨连接蛋白和骨激活素的表达可以诱导自发转移和肿瘤细胞沿穿透血管侵入脑内。 假设：我们假设骨连接蛋白和骨活化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。为了进一步明确骨连接蛋白和骨激活蛋白在脑胶质瘤病理生理学中的作用，阐明骨连接蛋白和骨激活蛋白的作用机制，为开发针对骨连接蛋白和骨激活蛋白的新型治疗药物奠定基础，我们将围绕以下两个具体目标展开研究： 1)明确骨连接蛋白和骨活化素在脑胶质瘤侵袭表型中的作用。2)验证骨连接蛋白和骨活化素作为脑胶质瘤侵袭的潜在治疗靶点。 希望这些研究将为恶性胶质瘤患者提供新的治疗措施的基础。