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: 8391584
• 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/8391584
• 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; public health relevance; 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.

描述（由申请人提供）： VA医疗保健系统迫切需要神经保护疗法，可用于促进创伤性脑损伤、中风和神经退行性疾病后的神经元存活。减轻神经元损失的潜在领域集中在与神经元损伤相关的神经炎症过程的调节元件上。已显示在神经炎症和神经元损失中起主要作用的有希望的靶点是酶环氧合酶2（考克斯-2），其催化前列腺素类合成中的限速步骤。在中风的动物模型中，当这种酶的活性被药理学或遗传学操作降低时，神经元存活率增加。然而，利用考克斯-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相关的心血管并发症。因此，最近的努力已经开始鉴定考克斯-2下游的靶点，例如前列腺素受体。最好的例子是前列腺素E2（PGE 2）的EP 1受体，它已被证明有助于兴奋性毒性后的神经元损伤。EP 1拮抗剂增加中风模型中和兴奋性毒性攻击后培养模型中的体外神经元存活。 其他炎症过程也会影响神经元的活力。在中枢神经系统（CNS）损伤后，炎性细胞如小胶质细胞迁移到损伤区域，并可使神经元对兴奋性毒性损伤更具抗性。然而，小胶质细胞如何与神经元相互作用，通过EP 1前列腺素受体调节神经元的活力知之甚少。我们最近发现，当存在小胶质细胞时，EP 1拮抗剂的神经保护作用丧失。这一发现表明，神经元EP 1对神经元活力的贡献可以由小胶质细胞调节，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。 基于我们的研究结果，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EP 1和EP 4受体来实现的。我们已经开发了一个功能强大的体外系统，使我们能够测试这种新的小胶质细胞之间的相互作用和参与神经元活力的重要信号通路。这项提议将测试这一假设，并可能确定新的神经保护策略集中在小胶质细胞的反应和调制的EP受体。具体目标1：确定小胶质细胞是否通过减弱神经元EP 1介导神经保护作用。具体目标#2：确定来自小胶质细胞的可溶性信号，这些信号改变神经元中的EP 1反应并增加神经元对NMDA的抗性。具体目标#3：确定小胶质细胞诱导的神经元核EP 1受体表达的丧失是否有助于增加神经元存活。具体目标#4：确定小胶质细胞活化程度如何通过调节神经元EP 1促进神经元活力。