Merlin regulation of glial cell growth and motility

描述（由申请人提供）：脑肿瘤是儿童和成人发病率和死亡率的重要来源。虽然脑肿瘤比其他形式的癌症更少见，但恶性脑肿瘤患者的平均生存期不到一年。治疗脑肿瘤患者的这种令人沮丧的成功率反映了对脑肿瘤形成和恶性进展重要的关键遗传和分子变化的基本理解。我们为这些毁灭性的癌症设计更好的治疗方法的能力在很大程度上依赖于对驱动肿瘤形成和进展的关键分子变化的识别。患有遗传性肿瘤易感综合征，2型神经纤维瘤病（NF2）的个体，会发展成室管膜瘤和脊柱星形细胞瘤。室管膜瘤和星形细胞瘤都是由肿瘤胶质细胞引起的胶质细胞恶性肿瘤（胶质瘤）。包括我们自己的实验室在内的几个实验室的研究表明，NF2基因失活和NF2基因产物梅林或神经鞘蛋白的表达缺失，代表了室管膜瘤中最常见的遗传变化，无论是在NF2患者还是散发性室管膜瘤患者中。我的初步研究，使用nf2缺陷的胶质细胞，已经证明梅林调节星形胶质细胞的生长和运动。nf2缺失的星形胶质细胞显示Src及其下游效应物FAK和paxillin的激活增加，所有这些先前都被证明参与细胞生长和运动的调节。此外，我发现在nf2缺失的胶质细胞中，merlin对生长和运动的调节依赖于src。在本提案中，我计划验证merlin通过调节Src活性来控制胶质细胞生长和运动的假设。具体来说，我将(1)确定梅林如何调节Src癌蛋白活性，(2)确定梅林依赖的Src调控如何控制胶质细胞生长和运动。这些研究的重点是确定神经系统中梅林生长调节的机制，这与确定未来治疗性抗癌药物设计的靶点有关。总的来说，这些实验旨在阐明脑肿瘤中一个关键的生长控制途径。这些实验对于确定治疗药物设计的潜在靶点至关重要，这些靶点旨在改善脑肿瘤中的一种生长控制缺陷，这可能会改善这些致命的人类癌症的治疗方法。

DESCRIPTION (provided by applicant): Brain tumors represent a significant source of morbidity and mortality in both children and adults. While brain tumors are less common than other forms of cancer, the mean survival of patients with malignant brain tumor is less than one year. This dismal success rate in treating patients with brain tumors reflects a rudimentary understanding of the key genetic and molecular changes important for brain tumor formation and malignant progression. Our ability to design better therapies for these devastating cancers is heavily dependent on the identification of the critical molecular changes that drive tumor formation and progression. Individuals with the inherited tumor predisposition syndrome, neurofibromatosis type 2 (NF2), develop ependymomas and spinal astrocytomas. Both ependymomas and astrocytomas are glial cell malignancies (gliomas) that arise from neoplastic glial cells. Studies from several laboratories, including our own, have shown that NF2 gene inactivation and loss of expression of the NF2 gene product, merlin or schwannomin, represents the most common genetic change in ependymoma, both in individuals with NF2 as well as in individuals with sporadic ependymoma. My preliminary studies, using Nf2-deficient glial cells, have demonstrated that merlin regulates growth and motility in astrocytes. Nf2-deficient astrocytes show increased activation of Src and its downstream effectors FAK and paxillin, all previously shown to be involved in the regulation of cell growth and motility. In addition, I showed that merlin regulation of growth and motility in Nf2-deficient glial cells is Src-dependent. In this proposal, I plan to test the hypothesis that merlin functions to control cell growth and motility in glia by regulating Src activity. Specifically, I will (1) determine how merlin regulates Src oncoprotein activity and (2) determine how merlin-dependent Src regulation controls glial cell growth and motility. These studies are focused on defining the mechanism underlying merlin growth regulation in the nervous system relevant to identifying targets for future therapeutic anti-cancer drug design. Collectively, these experiments are directed towards elucidating one of the key growth control pathways de-regulated in brain tumors. These experiments will be critical for the identification of potential targets for therapeutic drug design aimed at ameliorating one of the growth control defects in brain tumors, which may lead to improved treatments for these deadly human cancers.