Role of IRF-1 dependent chemokines in glioma

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是一种高度侵袭性和恶性的原发脑。尽管目前积极的治疗包括手术切除，然后进行放疗和化疗，但GBM的复发率很高，只有3%-5%的患者存活超过3年。GBM难以治疗，因为它迅速扩散到整个大脑，形成一个由GBM启动的促炎状态的肿瘤微环境，其特征是存在由GBM细胞和GBM激活的星形胶质细胞分泌的细胞因子，如IL-1。我们的初步数据表明，IL-1诱导星形胶质细胞表达转录因子干扰素调节因子-1(IRF-1)。新合成的IRF-1随后被激活，并诱导强大的趋化因子CCL5和CXCL10的表达。IRF-1的激活机制尚不清楚；然而，其他IRF通过其K63连接的多泛素化和磷酸化来激活。我们的初步数据表明，IL-1诱导K63连接的IRF-1的多泛素化，这是其激活所必需的。虽然已经报道了IRF-1的磷酸化，但尚不清楚它是否也是激活IRF-1所必需的。星形胶质细胞中IRF-1依赖的CCL5和CXCL10的表达可能影响GBM的进展。虽然这两种趋化因子通常与单核细胞和T淋巴细胞趋化有关，但它们都能促进GBM的增殖。因此，我们的中心假设是星形胶质细胞对IL-1的反应是上调依赖于IRF-1的趋化因子CXCL10和CCL5的表达，从而促进体内GBM细胞的增殖、迁移和侵袭。目的1：确定IRF-1的磷酸化是否是IL-1激活IRF-1的关键步骤。目的：探讨星形胶质细胞来源的CCL5和CXCL10在体外对大鼠肾小球系膜细胞增殖、迁移和侵袭的影响。目的3：确定IRF-1在小鼠肾小球基底膜发生和发展中的作用。完成这些目标将确定IRF-1、CXCL10和CCL5的激活是否有助于GBM的发展和进展。这也可能为未来疗法的发展带来新的目标。

DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) is a highly invasive and malignant primary brain. Despite aggressive treatment that currently includes surgical resection followed by radiation and chemotherapy, the recurrence of GBM is high with only 3-5% patients surviving longer than 3 years. GBM is refractory to treatment because it rapidly disseminates throughout the brain, develops a tumor microenvironment with GBM-initiated proinflammatory state characterized by the presence of cytokines, such as IL-1, which are secreted by both GBM cells and GBM-activated astrocytes. Our preliminary data show that IL-1 induces expression of transcription factor interferon regulatory factor 1 (IRF-1) in astrocytes. Newly synthesized IRF-1 is subsequently activated and induces the expression of potent chemokines CCL5 and CXCL10. The mechanism of IRF-1 activation remains elusive; however, other IRFs are activated by their K63-linked polyubiquitination and phosphorylation. Our preliminary data demonstrate that IL-1 induces K63-linked polyubiquitination of IRF-1 that is needed for its activation. Although, phosphorylation of IRF-1 has been reported, it is not clear whether it is also required for IRF-1 activation. IRF-1-dependent expression of CCL5 and CXCL10 in astrocytes likely affects GBM progression. Although both of these chemokines are commonly associated with monocyte and T lymphocyte chemotaxis, they both can increase GBM proliferation. Thus, our central hypothesis is that in response to IL-1, astrocytes upregulate expression of IRF-1-dependent chemokines CXCL10 and CCL5, which promote the proliferation, migration, and invasion of GBM cells in vivo. We propose the following aims to test this hypothesis: Aim 1: Determine whether phosphorylation of IRF-1 is a critical step in the activation of IRF-1 by IL-1. Aim 2: Evaluate the effect of astrocyte-derived CCL5 and CXCL10 on GBM proliferation, migration, and invasion in vitro. Aim 3: Determine the role of IRF-1 in both GBM development and progression in vivo. Completion of these aims will establish whether activation of IRF-1, CXCL10, and CCL5 contributes to GBM development and progression. It may also lead to new targets for the development of therapies in the future.