Targeting CNTF to increase adult forebrain neurogenesis

项目摘要。睫状神经营养因子介导的增加SVZ神经发生发生在小鼠脑后， 缺血性中风我们将继续研究星形胶质细胞中JNK抑制CNTF表达， 在幼稚小鼠中的神经发生，以测试用JNK抑制剂的全身性治疗是否可以增加神经发生 中风后我们还将阻断高度相关的促炎配体IL-6，我们发现它可以减少中风- 用GP 130抑制剂诱导神经发生。其次，我们发现血液中的玻连蛋白水平 (VTN)由肝脏产生，仅在中风后女性中增加，并泄漏到SVZ中以诱导IL-6和IL-10。 抑制神经反应我们将确定调节VTN的机制，重点是迷走神经 刺激毒蕈碱受体和FAK。第三，我们发现，在男性，阉割造成了一个 通过增加前神经源性CNTF的基础水平和降低 白细胞介素-6（IL-6）是有害的，并且在MCAO后保留。我们将定义不同的信号通路 作为这种男性特异性机制的基础，并测试睾酮的药理学阻断是否会 增加雄性的神经发生。目的1将确定gp 130抑制剂是否促进神经发生， 在成年和老年小鼠中风后6小时或2个月给予，以及它是否通过阻断IL-6起作用。我们将 还确定JNK抑制是否会通过增加CNTF来增加中风后的神经发生，和/或 JNK抑制剂是否会进一步增强MCAO后SC 144的神经原性作用。目标2将定义 调节肝脏VTN的潜在女性特异性机制，包括FAK和毒蕈碱乙酰胆碱 受体，测试药理FAK抑制和神经系统的作用，对肝脏的神经支配 在MCAO之后。目的3将确定介导睾酮对CNTF、LIF和IL-1影响的信号通路。 6的表达，并采用去势后脑内注射睾酮， 没有FAK，JNK，ERK或p38抑制剂，以及睾酮阻滞剂是否可以促进神经发生后， MCAO。这些研究将建立在我们以前的工作，以确定新的基本细胞内信号 抑制和增强参与SVZ神经发生的关键细胞因子CNTF和IL-6的机制 中风后

Project Summary. CNTF mediates the increased SVZ neurogenesis that occurs in the mouse brain after ischemic stroke. We will follow up on our finding that JNK in astrocytes represses CNTF expression and neurogenesis in naïve mice, to test whether systemic treatment with JNK inhibitor can increase neurogenesis after stroke. We will also block the highly related pro-inflammatory ligand IL-6, which we found reduces stroke- induced neurogenesis, with a gp130 inhibitor. Secondly, we have discovered that blood levels of vitronectin (VTN), produced by the liver, only increase in females after stroke, and leaks into the SVZ to induce IL-6 and repress the neurogenic response. We will identify the mechanisms that regulate VTN, focusing on vagal nerve stimulated muscarinic receptors and FAK. Thirdly, we discovered in males that castration caused an unexpected and very robust effect by increasing basal levels of pro-neurogenic CNTF and decreasing detrimental IL-6, and that this was retained after MCAO. We will define the differential signaling pathways underlying this male-specific mechanism and test whether pharmacological blocking of testosterone would increase neurogenesis in males. Aim 1 will determine whether a gp130 inhibitor promotes neurogenesis when given at 6 h or 2 months after a stroke in adult and aged mice, and whether it acts by blocking IL-6. We will also determine whether JNK inhibition would increase neurogenesis after stroke by increasing CNTF, and/or whether JNK inhibitor would further enhance the neurogenic effects of SC144 after MCAO. Aim 2 will define potentially female-specific mechanisms that regulate liver VTN, including FAK and muscarinic acetylcholine receptors, testing pharmacological FAK inhibition and the role of the nervous system innervation of the liver after MCAO. Aim 3 will define the signaling pathways that mediate testosterone’s effects on CNTF, LIF and IL- 6 expression in the SVZ after MCAO, and using intracerebral injection of testosterone after castration, with or without FAK, JNK, ERK or p38 inhibitors, and whether a testosterone blocker can promote neurogenesis after MCAO. These studies will build on our previous work to define novel fundamental intracellular signaling mechanisms that repress and enhance the key cytokines CNTF and IL-6 involved in SVZ neurogenesis following stroke.