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）： 退伍军人管理局医疗保健系统迫切需要可用于促进创伤性脑损伤、中风和神经退行性疾病后神经元存活的神经保护疗法。减轻神经元损失的一个潜在领域集中在调节与神经元损伤相关的神经炎症过程的要素。环氧合酶 2 (COX-2) 是一个有前途的靶标，已被证明在神经炎症和神经元损失中发挥重要作用，它催化前列腺素合成中的限速步骤。在中风的动物模型中，当通过药理学或基因操作降低这种酶的活性时，可以看到神经元存活率增加。然而，由于与使用这些药物相关的心血管并发症，利用 COX-2 抑制剂的神经保护疗法存在问题。因此，最近的努力已经开始确定 COX-2 下游的靶标，例如前列腺素受体。最好的例子是前列腺素 E2 (PGE2) 的 EP1 受体，它已被证明会导致兴奋性毒性后的神经元损伤。 EP1拮抗剂可增加中风模型和体外培养模型中兴奋性毒性攻击后神经元的存活率。 其他炎症过程也会影响神经元活力。中枢神经系统 (CNS) 受伤后，小胶质细胞等炎症细胞会迁移到受伤区域，使神经元对兴奋性毒性损伤具有更强的抵抗力。然而，关于小胶质细胞如何与神经元相互作用，通过 EP1 前列腺素受体调节神经元活力，人们知之甚少。我们最近发现，当小胶质细胞存在时，EP1 拮抗剂的神经保护作用就会消失。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，并且在体内小胶质细胞与神经元损伤相关的情况下具有重要意义。 根据我们的发现，我们假设小胶质细胞赋予的神经保护特性是通过改变神经元中的 EP1 和 EP4 受体来实现的。我们开发了一个强大的体外系统，使我们能够测试小胶质细胞和涉及神经元活力的重要信号通路之间的这种新型相互作用。该提案将检验这一假设，并可能确定以小胶质细胞反应和 EP 受体调节为中心的新神经保护策略。具体目标：具体目标#1：确定小胶质细胞是否通过减弱神经元 EP1 介导神经保护作用。具体目标#2：识别来自小胶质细胞的可溶性信号，这些信号改变神经元中的 EP1 反应并增加神经元对 NMDA 的抵抗力。具体目标#3：确定小胶质细胞诱导的神经元核 EP1 受体表达丧失是否有助于增加神经元存活率。具体目标#4：确定小胶质细胞激活程度如何通过调节神经元 EP1 来影响神经元活力。 公共卫生相关性： 退伍军人事务部医疗保健系统迫切需要促进创伤性脑损伤、脊髓损伤、中风和神经退行性疾病后神经元存活的治疗方法。潜在新疗法的一个有前景的领域可能是针对调节大脑中导致神经元损伤的炎症成分。我们发现大脑中一种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。前列腺素由环氧合酶 2 (COX-2) 产生，COX-2 抑制剂可以保护神经元。然而，利用 COX-2 抑制剂的治疗存在问题，因为与其使用相关的心血管并发症。因此，最近的努力已经开始确定 COX-2 下游的靶标，例如前列腺素受体。我们开发了一个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。这项工作可能会确定以小胶质细胞反应和 EP 受体调节为中心的新神经保护策略。