Lysophospholipids in Radiation Induced Signal Transduction in Malignant Gliomas

溶血磷脂在恶性胶质瘤辐射诱导信号转导中的作用

• 批准号: 8079087
• 负责人: DENNIS E HALLAHAN
• 金额: $ 30.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079087
• 关键词: Acids; Adult; Binding; Brain Stem; Cell Survival; Cells; Child; Cytosolic Phospholipase A2; Data; Diffusion; Disease; Disease Progression; Dose; Edema; Enzymes; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glioblastoma; Glioma; Glucocorticoids; Goals; Interruption; Ionizing radiation; Knock-out; Lipids; Lysophosphatidylcholines; Lysophospholipids; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Midbrain structure; Modality; Modeling; Molecular Target; Mus; Outcome; Pathway interactions; Perfusion; Phospholipase; Physiological; Play; Prevention; Production; Radiation; Radiation therapy; Receptor Activation; Receptor Signaling; Research; Resected; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Therapeutic; Unresectable; Vascular Endothelium; Vascular Permeabilities; alkylglycerophosphoethanolamine phosphodiesterase; angiogenesis; cancer therapy; cell motility; cytotoxicity; improved; inhibitor/antagonist; irradiation; knock-down; lysophosphatidic acid; migration; mouse model; neoplastic cell; novel; prevent; public health relevance; receptor; response; second messenger; tumor

DESCRIPTION (provided by applicant): Unresectable high grade gliomas are nearly incurable in both children and adults. In fact, brain stem and mid- brain gliomas in children and GBM in adults are nearly universally fatal. The primary treatment modality for these tumors is radiotherapy with glucocorticoids with or without Temizolamide. This treatment prolongs survival but has little impact upon 5 year survival unless tumors are first resected. Recently, the enzyme autotoxin (lysophospholipase-D; LysoPLD) has been found to be over expressed in high grade gliomas. This enzyme converts lysophosphocholine (LPC) to lysophosphatetic acid (LPA) which in turn binds to LPA receptors expressed in GBM. LPA receptors are G-protein coupled receptors (GPCRs) that activate cell invasion, migration and enhance cell viability. We have recently shown that the substrate for LysoPLD, LPC, is induced by 2 Gy x-irradiation. Cytosolic phospholipase A2 (cPLA2) is activated by 2 Gy and knock down, knock out or inhibition of cPLA2 improves the cytotoxicity of ionizing radiation. We propose therefore, that the mechanism by which this signal transduction pathway improves cell viability is by conversion of LPC to LPA and subsequent LPA receptor activation. We propose that inhibition of conversion of LPC to LPA or inhibition of LPA receptors in malignant gliomas will improve outcome in this lethal disease. To test these hypotheses, we will: 1. Study the role of LysoPLD in the conversion of LPC to LPA in irradiated malignant glioma models. 2. Study the role of LPA receptors in both malignant gliomas and tumor vascular endothelium. 3. Determine whether knock down, knock out or inhibition of Lyso PLD or LPA receptors improves tumor response to ionizing radiation. These studies will help to identify novel radiation induced signal transduction pathways and potential molecular targets to improve the outcome of high grade gliomas. PUBLIC HEALTH RELEVANCE: The goal of this research is to determine the role of Lysophospholipids in the radiation response in malignant gliomas. We will study the conversion of LPC to LPA and subsequent signaling through the LPA receptor in mouse glioma models and determine whether inhibitors of the LysoPLD enzyme prevents conversion to LPA. We will also determine whether inhibitors of this signaling pathway enhance the efficacy of radiotherapy in the treatment of glioblastoma models in the mouse.

描述(由申请人提供)：无法切除的高级别胶质瘤在儿童和成人中几乎都是无法治愈的。事实上，儿童的脑干和中脑胶质瘤以及成人的基底膜几乎都是致命的。这些肿瘤的主要治疗方法是糖皮质激素加或不加替硝唑胺的放射治疗。这种治疗延长了生存期，但除非首先切除肿瘤，否则对5年生存期几乎没有影响。最近发现，酶自身毒素(溶血磷脂酶-D；LysoPLD)在高级别胶质瘤中过度表达。这种酶将溶血磷胆碱(LPC)转化为溶血磷酸(LPA)，后者又与GBM中表达的LPA受体结合。LPA受体是G蛋白偶联受体(GPCRs)，能激活细胞的侵袭、迁移和提高细胞活力。我们最近发现，LPC的底物是由2Gyx辐射诱导的。胞浆磷脂酶A2(CPLA2)在2Gy射线照射下被激活，通过敲除或抑制cPLA2可增强电离辐射的细胞毒作用。因此，我们认为，这种信号转导途径提高细胞活力的机制是通过将LPC转化为LPA并随后激活LPA受体。我们认为，在恶性胶质瘤中抑制LPC向LPA的转化或抑制LPA受体将改善这种致命疾病的预后。为了验证这些假说，我们将：1.研究LysoPLD在辐射恶性胶质瘤模型中LPC向LPA转化过程中的作用。2.研究LPA受体在恶性胶质瘤和肿瘤血管内皮细胞中的作用。3.确定敲除、敲除或抑制Lyso PLD或LPA受体是否能提高肿瘤对电离辐射的反应。这些研究将有助于确定新的辐射诱导信号转导途径和潜在的分子靶点，以改善高级别胶质瘤的预后。 公共卫生相关性：这项研究的目标是确定溶血磷脂在恶性胶质瘤放射反应中的作用。我们将在小鼠胶质瘤模型中研究LPC向LPA的转化以及随后通过LPA受体的信号传递，并确定LysoPLD酶的抑制剂是否阻止向LPA的转化。我们还将确定该信号通路的抑制剂是否增强了放射治疗小鼠胶质母细胞瘤模型的疗效。