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：
10619621
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/10619621
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 Ligands Liver MAPK8 gene Male Castration Measures Mediating Middle Cerebral Artery Occlusion Molecular Target Motor Mus Muscarinic Acetylcholine Receptor Muscarinic Agonists Nerve Nervous System PTK2 gene Pericytes Pharmaceutical Preparations Pharmacotherapy Plasma Play Population Property Prosencephalon Regulation Repression Role Signal Pathway Signal Transduction Stroke 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 inhibitor insight male men nerve supply nervous system disorder neuroblast neurogenesis novel p38 Mitogen Activated Protein Kinase pharmacologic post stroke receptor response sex sexual dimorphism stem cell division subventricular zone translational study young adult

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 介导小鼠大脑中 SVZ 神经发生的增加。我们将继续研究星形胶质细胞中 JNK 抑制 CNTF 表达的发现。首次实验小鼠的神经发生，以测试 JNK 抑制剂的全身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。使用 gp130 抑制剂诱导神经发生其次，我们发现玻连蛋白的血液水平。 (VTN)，由肝脏产生，仅在女性中风后增加，并渗入 SVZ 诱导 IL-6 和我们将确定调节 VTN 的机制，重点关注迷走神经。刺激毒蕈碱受体和 FAK 第三，我们发现男性的去势会导致通过增加促神经源性 CNTF 的基础水平并降低不健康的 IL-6，并且在 MCAO 后保留，我们将定义差异信号通路。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目标 1 将确定 gp130 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。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 抑制剂是否会在 MCAO 后进一步增强 SC144 的神经源性作用将得到确定。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，测试药理学 FAK 抑制和肝脏神经系统神经支配的作用 MCAO 之后，目标 3 将定义介导睾酮对 CNTF、LIF 和 IL- 影响的信号通路。 MCAO 后 SVZ 中表达 6，并在去势后脑内注射睾酮，或没有 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这些研究将建立在我们之前的工作的基础上，以定义新的基本细胞内信号传导。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。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ciliary neurotrophic factor is a key sex-specific regulator of depressive-like behavior in mice.

睫状神经营养因子是小鼠抑郁样行为的关键性别特异性调节剂。

DOI：
发表时间：
2019
期刊：
影响因子：
3.7
作者：
Jia, Cuihong;Brown, Russell W;Malone, Hannah M;Burgess, Katherine C;Gill, W Drew;Keasey, Matthew P;Hagg, Theo
通讯作者：
Hagg, Theo

Endogenous CNTF mediates stroke-induced adult CNS neurogenesis in mice.

内源性 CNTF 介导小鼠中风诱导的成年 CNS 神经发生。