The role of KIF9 in glioma invasion

描述（由申请人提供）：肿瘤细胞侵入脑的局部正常区域在胶质瘤恶性中起关键作用。由于手术切除足够的边缘以捕获这些侵袭性细胞的局限性，胶质瘤在治疗后很可能复发。更好地理解胶质瘤细胞侵袭的机制可能使胶质瘤的治疗更有效。小胶质细胞可以增强胶质瘤的侵袭，并且胶质瘤中这些髓样细胞的较高水平与较差的预后相关。因此，更好地了解小胶质细胞刺激胶质瘤侵袭的机制可能为治疗提供新的机会。该提案将讨论以下方面的潜在作用： KIF9基因的产物在小胶质细胞刺激胶质瘤侵袭中的作用。KIF9基因编码驱动蛋白家族成员，神经胶质瘤中KIF9的过表达与较短的生存期相关。驱动蛋白与细胞成分沿沿着微管的运动有关。在初步研究中，我们发现KIF9的抑制减少了小胶质细胞刺激的胶质瘤侵袭和与基质降解相关的蛋白酶的分泌。因此，我们假设KIF9通过使基质蛋白水解酶能够运输到质膜进行分泌，从而增强侵袭能力，从而促进胶质瘤侵袭。KIF9在入侵中的作用将在两个特定目标中进行测试。在目的1中，我们将评估KIF9对小胶质细胞刺激的胶质瘤体外侵袭的重要性。在目标2中，我们将使用颅内注射来测试KIF9对于体内侵袭的重要性。如果成功，这笔赠款将确立KIF9作为开发新疗法的潜在新靶点的价值。

DESCRIPTION (provided by applicant): A critical role in glioma malignancy is played by invasion of the tumor cells into local, normal regions of the brain. Because of the limitations on surgery to remove adequate margins to capture these invasive cells, glioma is highly likely to recur after treatment. A better understanding of the mechanisms by which glioma cells invade may enable more effective treatment of glioma. Microglia can enhance glioma invasion, and higher levels of these myeloid cells in gliomas correlates with worse prognosis. A better understanding the mechanisms by which microglia can stimulate glioma invasion could therefore provide new opportunities for treatment. This proposal will address the potential role of the product of the KIF9 gene in microglial stimulation of glioma invasion. The KIF9 gene encodes a kinesin family member and overexpression of KIF9 in gliomas is correlated with shorter survival. Kinesins are associated with movement of cellular components along microtubules. In preliminary studies, we find that suppression of KIF9 reduces microglia-stimulated glioma invasion and secretion of proteases associated with matrix degradation. We therefore hypothesize that KIF9 contributes to glioma invasion through enabling the trafficking of matrix proteolytic enzymes to the plasma membrane for secretion, resulting in enhanced invasive capabilities. The role of KIF9 in invasion will be tested in two specific aims. In Aim 1, we will evaluate the importance of KIF9 for microglia-stimulated glioma invasion in vitro. In Aim 2, we will use intracranial injection to test the importance of KIF9 for invasion in vivo. If successful, this grant will establish the value of KIF9 as a potential new target for the development of novel therapeutics.