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

基本信息

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
项目类别：
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

项目摘要

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）：儿童和成人几乎无法治愈，无法切除的高级神经膜瘤几乎无法治愈。实际上，成人儿童和GBM中的脑干和中脑神经胶质瘤几乎是普遍致命的。这些肿瘤的主要治疗方式是糖皮质激素的放射疗法，有或不含钠糖苷。这种治疗延长了生存，但对5年生存的影响很小，除非首先切除肿瘤。最近，发现酶自毒素（溶血磷脂酶-d; lysopld）在高级胶质瘤中过度表达。该酶将溶血磷胆碱（LPC）转化为溶物磷酸（LPA），而溶血磷酸（LPA）又与GBM中表达的LPA受体结合。 LPA受体是G蛋白偶联受体（GPCR），可激活细胞浸润，迁移并增强细胞活力。我们最近表明，lysopld，LPC的底物是由2 Gy X-radiation诱导的。通过2 Gy激活胞质磷脂酶A2（CPLA2），并击倒，敲除或抑制CPLA2可改善电离辐射的细胞毒性。因此，我们提出，该信号转导途径提高细胞活力的机制是通过将LPC转化为LPA和随后的LPA受体激活。我们建议抑制LPC向LPA转化或在恶性神经胶质瘤中抑制LPA受体的抑制作用将改善这种致命疾病的结果。为了检验这些假设，我们将：1。研究lysopld在LPC转化为LPA在辐照恶性神经胶质瘤模型中的作用。 2。研究LPA受体在恶性神经胶质瘤和肿瘤血管内皮中的作用。 3。确定敲低，敲除还是抑制Lyso PLD或LPA受体可以改善肿瘤对电离辐射的反应。这些研究将有助于鉴定新的辐射诱导的信号转导途径和潜在的分子靶标，以改善高级神经胶质瘤的结果。公共卫生相关性：这项研究的目的是确定溶物磷脂在恶性神经胶质瘤中辐射反应中的作用。我们将研究LPC到LPA的转化以及随后通过LPA受体在小鼠胶质瘤模型中的信号传导，并确定lysopld酶的抑制剂是否阻止转化为LPA。我们还将确定该信号通路的抑制剂是否增强了放射疗法在小鼠中胶质母细胞瘤模型治疗中的功效。