Targeting CNTF to increase adult forebrain neurogenesis

项目摘要。CNTF介导小鼠脑内SVZ神经发生的增加 缺血性中风。我们将跟进我们的发现，星形胶质细胞中的JNK抑制CNTF的表达和 幼稚小鼠的神经发生，以测试全身应用JNK抑制剂是否能增加神经发生 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gp130抑制剂诱导神经再生。其次，我们发现血液中的玻璃体凝集素水平 (VTN)由肝脏产生，仅在女性中风后增加，并泄漏到SVZ诱导IL-6和 抑制神经源性反应。我们将确定VTN的调节机制，重点是迷走神经 刺激M受体和FAK。第三，我们在男性身上发现，阉割会导致 通过增加神经源性CNTF的基础水平和降低 有害的IL-6，并在大脑中动脉阻塞后保留。我们将定义差异信号通路 这种男性特有的机制，并测试药物阻断睾丸素是否会 增加男性的神经发生。目标1将确定gp130抑制剂在以下情况下是否促进神经发生 在成年和老年小鼠中风后6小时或2个月给药，以及它是否通过阻断IL-6起作用。我们会 还要确定抑制JNK是否会通过增加CNTF和/或增加中风后的神经再生 JNK抑制剂是否会进一步增强SC144在MCAO后的神经发生作用。目标2将定义 潜在的女性特有的调节肝脏VTN的机制，包括FAK和M碱乙酰胆碱 受体，测试药物对FAK的抑制作用和神经系统对肝脏的作用 在MCAO之后。目标3将定义介导睾酮对CNTF、LIF和IL-1影响的信号通路。 6大脑中动脉结扎后SVZ的表达，去势后脑内注射睾酮，或 在没有FAK、JNK、ERK或p38抑制剂的情况下，睾酮阻滞剂是否可以促进神经再生 MCAO.这些研究将建立在我们之前工作的基础上，以定义新的基本细胞内信号 抑制和增强关键细胞因子CNTF和IL-6参与SVZ神经发生的机制 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.