The role of KIF9 in glioma invasion

KIF9在胶质瘤侵袭中的作用

基本信息

批准号：
8934205
负责人：
JEFFREY E SEGALL
金额：
$ 20.88万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8934205
关键词：
Address Aftercare Biological Assay Brain region Caliber Cell membrane Cells Clinical Trials Conditioned Culture Media Data Databases Development Disease Enzymes Evaluation Family member Foundations Genes Glioma Grant Health Hela Cells Image Immunohistochemistry In Situ Nick-End Labeling In Vitro Injection of therapeutic agent Interstitial Collagenase Invaded Kinesin Lead Malignant Neoplasms Mammalian Cell Microglia Microtubules Mitotic Modeling Movement Myeloid Cells Nature Operative Surgical Procedures Paper Patients Peptide Hydrolases Pharmaceutical Preparations Play Property Proteins Role S-Phase Fraction Series Site Staining method Stains Structure Surgeon Testing Therapeutic Time Tumor Cell Invasion Work base chemotherapy effective therapy high risk improved in vitro Assay in vivo inhibitor/antagonist innovation macrophage neoplastic cell novel novel therapeutics outcome forecast overexpression paracrine trafficking tumor

项目摘要

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.

描述（由申请人提供）：在神经胶质瘤恶性肿瘤中发挥关键作用的是肿瘤细胞侵入大脑的局部正常区域。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，神经胶质瘤在治疗后很可能复发。更好地了解神经胶质瘤细胞侵袭的机制可能有助于更有效地治疗神经胶质瘤。小胶质细胞可以增强神经胶质瘤的侵袭，神经胶质瘤中这些骨髓细胞的水平较高与预后较差相关。因此，更好地了解小胶质细胞刺激神经胶质瘤侵袭的机制可以为治疗提供新的机会。该提案将解决以下方面的潜在作用： KIF9 基因在小胶质细胞刺激神经胶质瘤侵袭中的产物。 KIF9 基因编码驱动蛋白家族成员，神经胶质瘤中 KIF9 的过度表达与较短的生存期相关。驱动蛋白与细胞成分沿微管的运动有关。在初步研究中，我们发现抑制 KIF9 可以减少小胶质细胞刺激的神经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 通过将基质蛋白水解酶运输到质膜进行分泌来促进神经胶质瘤侵袭，从而增强侵袭能力。 KIF9 在入侵中的作用将在两个特定目标上进行测试。在目标 1 中，我们将评估 KIF9 对于小胶质细胞刺激的体外神经胶质瘤侵袭的重要性。在目标2中，我们将通过颅内注射来测试KIF9对于体内侵袭的重要性。如果成功，这笔资助将确立 KIF9 作为开发新型疗法的潜在新靶点的价值。