Targeting CNTF to increase adult forebrain neurogenesis

靶向 CNTF 增加成人前脑神经发生

基本信息

批准号：
10406347
负责人：
THEO HAGG
金额：
$ 42.87万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406347
关键词：
Acetylcholine Acute Adult Affect Androgen Receptor Antibodies Astrocytes Binding Blood Brain Castration Cells Ciliary Neurotrophic Factor Data Female Flutamide Funding Genetic Grant Hepatocyte Hormones Human IL6ST gene In Vitro Inflammatory Injections Interleukin-6 Ischemic Stroke Knock-out LIF gene Lead Ligands Liver MAPK8 gene Male Castration Measures Mediating Middle Cerebral Artery Occlusion Molecular Target Motor Mus Muscarinic Acetylcholine Receptor Muscarinic Agonists Nerve Nervous system structure PTK2 gene Pericytes Pharmaceutical Preparations Pharmacology Pharmacotherapy Plasma Play Population Property Prosencephalon Regulation Repression Role Signal Pathway Signal Transduction Stroke Sum Testing Testosterone Translating Vagotomy Vagus nerve structure Vitronectin Woman Work aged antagonist brain cell cell type cytokine experimental study follow-up genetic approach improved outcome in vivo evaluation inhibitor insight male men nerve supply nervous system disorder neuroblast neurogenesis novel p38 Mitogen Activated Protein Kinase post stroke receptor response sex sexual dimorphism stem cell division subventricular zone translational study young adult

Acetylcholine Acute Adult Affect Androgen Receptor Antibodies Astrocytes Binding Blood Brain Castration Cells Ciliary Neurotrophic Factor Data Female Flutamide Funding Genetic Grant Hepatocyte Hormones Human IL6ST gene In Vitro Inflammatory Injections Interleukin-6 Ischemic Stroke Knock-out LIF gene Lead Ligands Liver MAPK8 gene Male Castration Measures Mediating Middle Cerebral Artery Occlusion Molecular Target Motor Mus Muscarinic Acetylcholine Receptor Muscarinic Agonists Nerve Nervous system structure PTK2 gene Pericytes Pharmaceutical Preparations Pharmacology Pharmacotherapy Plasma Play Population Property Prosencephalon Regulation Repression Role Signal Pathway Signal Transduction Stroke Sum Testing Testosterone Translating Vagotomy Vagus nerve structure Vitronectin Woman Work aged antagonist brain cell cell type cytokine experimental study follow-up genetic approach improved outcome in vivo evaluation inhibitor insight male men nerve supply nervous system disorder neuroblast neurogenesis novel p38 Mitogen Activated Protein Kinase post stroke receptor response sex sexual dimorphism stem cell division subventricular zone translational study young adult

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项目摘要

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.

项目摘要。 CNTF介导了在小鼠大脑中发生的SVZ神经发生的增加缺血性中风。我们将跟进我们的发现，即星形胶质细胞中的JNK反映了CNTF的表达和幼稚小鼠的神经发生以测试使用JNK抑制剂的系统治疗是否可以增加神经发生中风后。我们还将阻止高度相关的促炎配体IL-6，我们发现这减少了中风 - 诱导神经发生，带有GP130抑制剂。其次，我们发现血液水平的玻璃体素水平（VTN），由肝脏产生，仅在中风后女性增加，并泄漏到SVZ中以诱导IL-6和抑制神经源反应。我们将确定调节VTN的机制，专注于迷走神经刺激的毒蕈碱受体和FAK。第三，我们在男性中发现cast割导致通过增加促核心CNTF的基本水平并减少，意外且非常健壮的效果有害的IL-6，这是在MCAO之后保留的。我们将定义差分信号通路这种男性特异性机制的基础，并测试睾丸激素的药理阻断是否会增加男性神经发生。 AIM 1将确定GP130抑制剂是否会促进神经发生在成年和老年小鼠中风后6小时或2个月后给予，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和/或 JNK抑制剂是否会进一步增强MCAO后SC144的神经源作用。 AIM 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，测试药物FAK抑制和肝脏神经神经的作用在MCAO之后。 AIM 3将定义介导睾丸激素对CNTF，LIF和IL-的影响的信号传导途径 6在MCAO之后的SVZ中表达6，并在cast割后使用脑内注射睾丸激素，没有FAK，JNK，ERK或p38抑制剂，以及睾丸激素阻滞剂是否可以促进神经发生 MCAO。这些研究将基于我们以前的工作，以定义新的基本细胞内信号传导反映和增强与SVZ神经发生有关的关键细胞因子CNTF和IL-6的机制下风。