Prostanoid Modulation of Neuronal Death

前列腺素对神经元死亡的调节

• 批准号: 6574064
• 负责人: Noel G. Carlson
• 金额: $ 15.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574064
• 关键词: cell death; enzyme activity; enzyme induction /repression; enzyme inhibitors; excitatory aminoacid; gene expression; glutamate receptor; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; neurons; neuroprotectants; nonsteroidal antiinflammatory agent; polymerase chain reaction; prostaglandin E; prostaglandin endoperoxide synthase; prostaglandin receptor; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Alzheimer's disease and stroke are common conditions in the aging population. Each of these conditions is characterized by neuronal death, and agents that might prevent this are of great importance. One highly promising approach in preventing neuronal death is through the use of inhibitors of the inducible form of the enzyme cyclooxygenase (COX-2), termed Non Steroidal Anti-Inflammatory Drugs (NSAIDs). However, the mechanism of how COX-2 contributes to neuronal death is not known. This proposal will use an in vitro neuronal culture system to examine the interactions between the COX-2 derived metabolite PG-E2 and neuronal death mediated by glutamate receptors activated by the specific agonist NMDA. We will examine how PG-E2 acting through either the EP1 or EP3 prostanoid receptors contributes to neuronal death. The underlying hypothesis is that inhibition of the COX-2-generated prostanoid PG-E2 promotes neuronal survival during excitotoxic challenge by preventing activation of the EP1 receptor that contributes to neuronal death. The key questions which will be addressed in this proposal using an in vitro neuronal culture system are: 1) Do other PG-E receptor drugs modulate neuronal death as would be predicted by their interactions with EPI? 2) What is the expression pattern of the PG-E receptors (EP-1) as they may relate to neuronal death? 3) Is the contribution to neuronal death (or survival) by PG-E2 mediated through non-neuronal cells such as astrocytes? 4) What interactions between COX and PG-E2 contribute to the neuroprotective versus neurodestructive properties of PG-E2? 5) What is the influence by PG-E2 on the neuronal gene expression profile? The specific objectives for this study are:Specific Aim #1. To examine which PG receptors in mixed neuronal cultures contribute to theneurodestructive (by antagonism of NSAID-mediated neuroprotection) verses neuroprotective (in theabsence of NSAID) actions of PC-E2. Specific Aim #2. To examine contribution of non-neuronal cells towards neuronal death mediated by PG's. It is the long-term goal that these studies will identify new targets downstream from COX in the metabolic pathway (such as the PG-E receptors) to develop safer and more effective strategies of neuroprotection that could be applied to treating neurodegenerative diseases.

描述（由申请人提供）：阿尔茨海默氏病和中风是老年人群中的常见病症。每一种疾病的特征都是神经元死亡，而能够预防这种情况的药物非常重要。预防神经元死亡的一种非常有前景的方法是使用诱导型环氧合酶 (COX-2) 抑制剂，称为非类固醇抗炎药 (NSAID)。然而，COX-2 导致神经元死亡的机制尚不清楚。该提案将使用体外神经元培养系统来检查 COX-2 衍生代谢物 PG-E2 与由特定激动剂 NMDA 激活的谷氨酸受体介导的神经元死亡之间的相互作用。我们将研究 PG-E2 如何通过 EP1 或 EP3 前列腺素受体发挥作用，导致神经元死亡。潜在的假设是，抑制 COX-2 生成的前列腺素 PG-E2 通过阻止导致神经元死亡的 EP1 受体激活，从而在兴奋性毒性挑战期间促进神经元存活。本提案将使用体外神经元培养系统解决的关键问题是：1）其他 PG-E 受体药物是否如通过与 EPI 相互作用所预测的那样调节神经元死亡？ 2) PG-E 受体 (EP-1) 的表达模式是什么，因为它们可能与神经元死亡有关？ 3) PG-E2 对神经元死亡（或存活）的贡献是通过非神经元细胞（如星形胶质细胞）介导的吗？ 4) COX 和 PG-E2 之间的哪些相互作用有助于 PG-E2 的神经保护和神经破坏特性？ 5) PG-E2 对神经元基因表达谱有何影响？本研究的具体目标是：具体目标#1。研究混合神经元培养物中哪些 PG 受体会导致 PC-E2 的神经破坏作用（通过拮抗 NSAID 介导的神经保护作用）与神经保护作用（在没有 NSAID 的情况下）。具体目标#2。研究非神经元细胞对 PG 介导的神经元死亡的贡献。这些研究的长期目标是确定代谢途径中 COX 下游的新靶点（例如 PG-E 受体），以开发更安全、更有效的神经保护策略，用于治疗神经退行性疾病。