MOLECULAR MOTORS IN NEUROONCOLOGY

间变性胶质瘤是脑内残留的恶性肿瘤。 令人沮丧的难以治疗。大多数人的平均存活率 这些肿瘤的恶性-多形性胶质母细胞瘤-不到一年， 即使是这组脑瘤中侵袭性较弱的成员 一般在2-4年内杀死受害者。这种情况是 由于间变性胶质瘤对 常规放疗和化疗药物的作用 有限数量的细胞目标。这反过来又辩称，另一个 胶质瘤细胞机制的组成部分，对恶性疾病有贡献 表型需要鉴定和研究，以期最终 开发可以抑制其功能从而阻止其功能的方法 恶性行为。这项提议的基本假设是 分子马达，一类以牺牲为代价产生运动的酶 三磷酸腺苷水解物，代表了这样一个成分。这些马达，谁的 在肿瘤学中的重要性一直被低估，尤其是 三种元素中的重要成分 胶质瘤-它们侵袭正常大脑的能力，它们产生 血液供应，以及它们在不可控的 举止。将提供数据，以确定抑制以下其中之一 这些马达-肌球蛋白II-与无毒药物一起阻止侵袭性， 研究这种马达蛋白的分子生理学产生了新的 对它是如何运作和受到监管的洞察。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(S) 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。将开发出各种方法，以便 测试分子遗传学方法阻断病毒感染的可行性 神经胶质瘤和血管内皮细胞中肌球蛋白II的原位活性。数据将 也是为了表明这些方法最终也可能 应用于其他分子马达，如驱动蛋白， 有丝分裂器官。

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.