Prostanoid Modulation of Neuronal Death

描述（由申请人提供）：阿尔茨海默病和中风是老年人群的常见疾病。每一种情况的特征都是神经元死亡，因此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希望的方法是通过使用酶环氧合酶（考克斯-2）的诱导型抑制剂，称为非甾体抗炎药（NSAID）。然而，考克斯-2如何参与神经元死亡的机制尚不清楚。本研究拟利用体外神经元培养系统研究考克斯-2衍生代谢产物PG-E2与特异性激动剂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EP 1或EP 3前列腺素受体作用于神经元死亡。潜在的假设是，抑制考克斯-2产生的前列腺素PG-E2通过阻止导致神经元死亡的EP 1受体的激活，促进兴奋性毒性攻击期间的神经元存活。本提案中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其与EPI的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）的作用是否通过非神经元细胞（如星形胶质细胞）介导？4)考克斯和PG-E2之间的相互作用对PG-E2的神经保护性和神经破坏性有何影响？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受体参与了PC-E2的神经破坏（通过拮抗NSAID介导的神经保护作用）和神经保护（在没有NSAID的情况下）作用。具体目标#2。检查非神经元细胞对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考克斯下游的新靶点（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。

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.