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: 8230628
• 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/8230628
• 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）：不可切除的高级别神经胶质瘤对于儿童和成人来说几乎无法治愈。事实上，儿童的脑干和中脑胶质瘤以及成人的 GBM 几乎都是致命的。这些肿瘤的主要治疗方式是糖皮质激素联合或不联合替米唑胺的放射治疗。这种治疗可延长生存期，但对 5 年生存率影响不大，除非首先切除肿瘤。最近，发现自毒素酶（溶血磷脂酶-D；LysoPLD）在高级神经胶质瘤中过度表达。这种酶将溶血磷酸胆碱 (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 (GPCR)，可激活细胞侵袭、迁移并增强细胞活力。我们最近表明，LysoPLD 的底物 LPC 是由 2 Gy x 辐射诱导的。胞质磷脂酶 A2 (cPLA2) 被 2 Gy 激活，敲低、敲除或抑制 cPLA2 可提高电离辐射的细胞毒性。因此，我们提出，该信号转导途径改善细胞活力的机制是通过 LPC 转化为 LPA 以及随后的 LPA 受体激活。我们建议抑制 LPC 转化为 LPA 或抑制恶性神经胶质瘤中的 LPA 受体将改善这种致命疾病的预后。为了检验这些假设，我们将： 1. 研究 LysoPLD 在受辐射的恶性神经胶质瘤模型中 LPC 转化为 LPA 的作用。 2. 研究LPA受体在恶性胶质瘤和肿瘤血管内皮中的作用。 3.确定Lyso PLD或LPA受体的敲除、敲除或抑制是否改善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标，以改善高级别胶质瘤的治疗结果。 公共健康相关性：本研究的目的是确定溶血磷脂在恶性神经胶质瘤放射反应中的作用。我们将研究小鼠神经胶质瘤模型中 LPC 向 LPA 的转化以及随后通过 LPA 受体的信号传导，并确定 LysoPLD 酶的抑制剂是否会阻止向 LPA 的转化。我们还将确定该信号通路的抑制剂是否可以增强放疗治疗小鼠胶质母细胞瘤模型的疗效。