MOLECULAR MOTORS IN NEUROONCOLOGY

间变性神经胶质瘤是大脑的恶性肿瘤， 令人沮丧地难以治疗。对于大多数人来说， 这些肿瘤的恶性-多形性胶质母细胞瘤-小于一年， 即使是这组脑瘤中攻击性较低的成员， 通常在2-4年内杀死受害者。这种状况是 由于间变性神经胶质瘤相对耐受 常规放射和化学治疗剂的作用， 有限数量的细胞目标。这反过来又表明， 神经胶质瘤细胞机器的组成部分，有助于恶性 需要对表型进行鉴定和研究，希望最终 开发抑制其功能的方法， 恶性行为这一建议的基本假设是， 分子发动机，一类酶， ATP的水解，代表这样一个组成部分。这些发动机， 在肿瘤学中的重要性被低估，特别是 恶性肿瘤的三个要素中的重要组成部分， 神经胶质瘤-它们侵入正常大脑的能力，它们产生 血液供应，以及它们在无法控制的情况下增殖的能力， 方式将提供数据，确定抑制其中一种 这些马达--肌球蛋白II--与无毒药物一起阻断了侵袭性， 研究这种马达蛋白的分子生理学， 了解它是如何运作和监管的。在这个项目中，我将 建议：1）更详细地研究肌球蛋白的具体作用， II在胶质瘤侵袭中的作用，以及2）检查 肌球蛋白II活性的调节。将制定方法， 测试分子遗传学方法的可行性， 胶质瘤和内皮细胞中肌球蛋白II的原位活性。数据将 也表明这些方法最终也可能 可以应用于其他分子马达，如驱动蛋白， 有丝分裂器

Anaplastic gliomas are malignant neoplasms of the brain that remain frustratingly difficult to treat. The mean survival for the most malignant of these tumors-glioblastoma multiforme-is less than one year, and even the less aggressive members of this group of brain tumors generally kill their victims within 2-4 years. This state of affairs is due to the fact that anaplastic gliomas are relatively resistant to the effects of conventional radiation and chemotherapy-agents which inhibit a limited number of cellular targets. This in turn argues that other components of the glioma cell machinery which contribute to the malignant phenotype need to be identified and studied, in the hope of eventually developing methods that could inhibit their function and thus block this malignant behavior. It is the underlying hypothesis of this proposal that molecular motors, a class of enzymes that produce movement at the expense of ATP hydrolysis, represent such a component. These motors, whose importance in oncology has been underappreciated, are particularly important components in three elements of the malignant repertoire of gliomas-their ability to invade normal brain, their ability to generate a blood supply, and their ability to proliferate in an uncontrollable manner. Data will be presented which establishes that inhibiting one of these motors-myosin II-with non-toxic drugs blocks invasiveness, and that studying the molecular physiology of this motor protein yields new insights into how it works and is regulated. In this project, I will propose to: 1) study in greater detail the specific role(s) that myosin II plays in glioma invasion, and 2) examine the molecular basis for the regulation of myosin II activity. Methods will be developed that will test the feasibility of molecular genetic approaches to blocking the activity of myosin II in situ in glioma and endothelial cells. Data will also be presented to suggest that these approaches may also ultimately be applied to other molecular motors, such as the kinesins, that power the mitotic apparatus.