Roles of microglia and prostaglandin receptors in neuroprotection

小胶质细胞和前列腺素受体在神经保护中的作用

• 批准号: 8047884
• 负责人: Noel G. Carlson
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047884
• 关键词: Accounting; Affect; Animal Model; Area; Brain; Cardiovascular system; Cells; Cessation of life; Coxibs; Dinoprostone; Drug usage; EP4 receptor; Elements; Enzymes; Glutamate Receptor; Goals; Healthcare Systems; In Vitro; Inflammation; Inflammatory; Injury; Investigation; Mediating; Membrane; Microglia; Modeling; Mus; N-Methylaspartate; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Neurons; Nuclear; Play; Process; Property; Prostaglandin Receptor; Prostaglandins; Resistance; Role; Signal Pathway; Signal Transduction; Spinal cord injury; Stimulus; Stream; Stroke; System; Testing; Time; Traumatic Brain Injury; Work; assault; attenuation; base; cyclooxygenase 2; enzyme activity; excitotoxicity; genetic manipulation; in vitro Model; in vivo; injured; neuroinflammation; neuron loss; neuronal survival; neuroprotection; novel; prostanoid receptor EP1; receptor; receptor expression; response

DESCRIPTION (provided by applicant): There is an urgent need in the VA health care system for neuroprotective therapies that can be applied to promote neuronal survival following traumatic brain injury, stroke and neurodegenerative disease. A potential area for mitigating neuronal loss centers on regulating elements of neuroinflammatory processes associated with neuronal injury. A promising target that has been shown to play a major role in neuroinflammation and neuronal loss is the enzyme cyclooxygenase 2 (COX-2) which catalyzes the rate- limiting step in the synthesis of prostanoids. In animal models of stroke, increased neuronal survival is seen when the activity of this enzyme is diminished by either pharmacological or genetic manipulation. However, neuroprotective therapies utilizing COX-2 inhibitors are problematic because of cardiovascular complications associated with the use of these drugs. As such, recent efforts have begun to identify targets down stream of COX-2 such as the prostanoid receptors. The best example of this is seen with the EP1 receptor for prostaglandin E2 (PGE2) which has been shown to contribute to neuronal injury following excitotoxicity. Antagonists of EP1 increase neuronal survival in stroke models and in vitro in culture models following excitotoxic assault. Other inflammatory processes can also affect neuronal viability. Following injury in the central nervous system (CNS), inflammatory cells such as microglia migrate to the injured area and can render neurons more resistant to excitotoxic insults. However, little is known about how microglia interact with neurons to modulate neuronal viability through the EP1prostanoid receptor. We recently discovered that the neuroprotective effect of EP1 antagonists is lost when microglia are present. This finding indicates that the contribution to neuronal viability by neuronal EP1 can be regulated by microglia and has important implications in vivo where microglia are associated with neuronal injury. Based on our findings, we hypothesize that the neuroprotective properties conferred by microglia are achieved by altering EP1 and EP4 receptors in neurons. We have developed a powerful in vitro system which enables us to test this novel interaction between microglia and an important signaling pathway involved in neuronal viability. This proposal will test the hypothesis and may identify new neuroprotective strategies centered on microglial responses and modulation of EP receptors. SPECIFIC OBJECTIVES: Specific Aim #1: Determine if microglia mediate neuroprotection through attenuation of neuronal EP1. Specific Aim #2: Identify the soluble signals from microglia that alter EP1 response in neurons and increase neuronal resistance to NMDA. Specific Aim #3: Determine if microglial-induced loss of neuronal nuclear EP1 receptor expression contributes to increased neuronal survival. Specific Aim #4: Determine how the degree of microglial activation contributes to neuronal viability through modulation of neuronal EP1. PUBLIC HEALTH RELEVANCE: There is an urgent need in the VA health care system for therapies that promote neuronal survival following traumatic brain injury, spinal cord injury, stroke and neurodegenerative disease. A promising area for potential new therapies may be directed at modulating components of inflammation in the brain that contribute to the injury of neurons. We have discovered that an inflammatory cell in the brain called microglia, may protect neurons by changing how neurons respond to other inflammatory molecules called prostanoids. Prostanoids are made by the enzyme cyclooxygenase 2 (COX-2) and inhibitors of COX-2 can protect neurons. However, therapies utilizing COX-2 inhibitors are problematic because of cardiovascular complications associated with their use. As such, recent efforts have begun to identify targets down stream of COX-2 such as the prostanoid receptors. We have developed a powerful neuronal culture system which enables us to test how microglia can change the EP1 prostanoid receptors that modulate neuronal viability. This work may identify new neuroprotective strategies centered on microglial responses and modulation of EP receptors.

描述（由申请人提供）： VA卫生保健系统迫切需要神经保护疗法，可用于促进脑损伤，中风和神经退行性疾病后促进神经元生存。缓解神经元损失的潜在区域，集中于调节与神经元损伤相关的神经炎症过程的元素。酶环氧酶2（COX-2）在神经炎症和神经元丧失中起着重要作用，它在神经炎症和神经元丧失中起着重要作用，该酶在合成前列腺素的合成中催化了速率限制步骤。在中风的动物模型中，当药理学或遗传操作减少该酶的活性时，会发现神经元存活增加。但是，使用COX-2抑制剂的神经保护疗法是有问题的，因为与使用这些药物有关的心血管并发症。因此，最近的努力已经开始鉴定出cox-2（例如前列腺素受体）的靶标。最好的例子是使用前列腺素E2（PGE2）的EP1受体（PGE2），该受体在兴奋性毒性后已显示出有助于神经元损伤。 EP1的拮抗剂在兴奋性毒性攻击后会增加中风模型中的神经元存活和体外培养模型。 其他炎症过程也会影响神经元的生存能力。在中枢神经系统（CNS）受伤后，小胶质细胞（例如小胶质细胞）迁移到受伤区域，并使神经元对兴奋性毒性损伤具有更耐药性。然而，关于小胶质细胞如何与神经元相互作用以通过EP1螺旋体受体调节神经元活力的知之甚少。我们最近发现，当存在小胶质细胞时，EP1拮抗剂的神经保护作用会丢失。这一发现表明，神经元EP1对神经元活力的贡献可以受到小胶质细胞的调节，并且在小胶质细胞与神经元损伤相关的体内具有重要意义。 根据我们的发现，我们假设通过改变神经元中的EP1和EP4受体来实现小胶质细胞所赋予的神经保护特性。我们已经开发了一个强大的体外系统，使我们能够测试小胶质细胞与神经元生存力涉及的重要信号通路之间的这种新型相互作用。该建议将检验该假设，并可以确定以小胶质响应和EP受体调节为中心的新神经保护策略。特定目标：特定目标＃1：确定小胶质细胞是否通过衰减神经元EP1介导神经保护作用。特定目标＃2：确定来自小胶质细胞的可溶信号，这些信号改变了神经元中EP1反应并增加对NMDA的神经元耐药性。特定目标＃3：确定小胶质细胞诱导的神经元核EP1受体表达的丧失是否有助于神经元存活增加。特定目标＃4：确定小胶质细胞活化程度如何通过调节神经元EP1来促进神经元的生存力。 公共卫生相关性： VA卫生保健系统迫切需要在脑损伤，脊髓损伤，中风和神经退行性疾病后促进神经元存活的疗法。潜在的新疗法的有前途的区域可以针对调节大脑中炎症的成分，从而导致神经元的损伤。我们发现，大脑中称为小胶质细胞的炎症细胞可以通过改变神经元对其他称为前列腺素的炎症分子的反应来保护神经元。前列腺素是由酶环氧酶2（COX-2）制成的，COX-2的抑制剂可以保护神经元。但是，使用COX-2抑制剂的疗法由于与使用相关的心血管并发症而有问题。因此，最近的努力已经开始鉴定出cox-2（例如前列腺素受体）的靶标。我们已经开发了一种强大的神经元培养系统，使我们能够测试小胶质细胞如何改变调节神经元活力的EP1前列腺素受体。这项工作可以确定以小胶质响应和EP受体调节为中心的新神经保护策略。