White matter protection by inhibitors of glial scar formation in perinatal hypoxia ischemia

围产期缺氧缺血时胶质疤痕形成抑制剂对白质的保护作用

基本信息

批准号：
10770210
负责人：
Stephen Arthur Back
金额：
$ 15.4万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10770210
关键词：
Address Adult Age Animals Antibodies Anxiety Astrocytes Behavior Behavioral Biological Bipolar Disorder Brain Brain Hypoxia-Ischemia Cell Adhesion Cell Communication Cell surface Cells Cerebral cortex Cicatrix Clinical Data Dendritic Spines Development Enzymes Extracellular Matrix Female Formulation Genes Genetic Transcription Glutamate Receptor Glutamate Transporter Glutamates Goals Golgi Apparatus Homeostasis Hyaluronan Hyaluronic Acid Intensive Care Knockout Mice Life Ligands Link Major Depressive Disorder Mediating Mental Health Mental disorders Metabotropic Glutamate Receptors Methods Modeling Modification Molecular Mus Neonatal Intensive Care Neurons Neurotransmitters Newborn Infant Outcome Performance Perinatal Hypoxia Phenotype Play Premature Birth Premature Infant Protein Analysis Protein Secretion Proteins Proteoglycan Protoplasm Regulation Research Research Proposals Risk Role Sample Size Schizophrenia Sex Differences Strategic Planning Survivors Synapses System United States National Institutes of Health Vertebral column Visualization Western Blotting Women&apos s Health age related behavioral outcome behavioral phenotyping brain behavior cohort critical period density glutamatergic signaling hippocampal pyramidal neuron improved inhibitor insight male mature animal metabotropic glutamate receptor 3 neonatal brain neonatal brain development neonate neural circuit neural network neurobehavioral neuron development neuronal cell body neuronal circuitry neuropsychiatric disorder neurotransmission non-affective psychoses novel parent grant postnatal postnatal development pre-clinical research response severe mental illness sex social white matter

项目摘要

Summary By adulthood, survivors of premature birth are at significantly increased risk for several forms of severe mental illness, including nonaffective psychosis, schizophrenia, major depressive disorder, and bipolar affective disorder. This preclinical research proposal seeks to define the role of sex-dependent factors that influence early life Extra Cellular Matrix (ECM)-mediated mechanisms that contribute to risks for mental illness in survivors of premature birth as they mature to adulthood. Our proposal thus aligns with strategic goals 1.1. and 1.4 of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research. We propose to define basic biological differences between male and female neonates that influence mechanisms relevant to enhanced risks for life-long mental illness in preterm survivors. During preterm neonatal brain development, we have found that the hyaluronic acid (HA) backbone of the ECM undergoes remodeling by the enzyme TSG-6 (TNF stimulated gene-6), which displays peak activity. Our preliminary studies support that remodeling of ECM HA by TSG-6 regulates transcriptional maturation of astrocytes which are integral to neuronal function. In knock out mice that lack TSG-6 activity, adults display alterations in anxiogenic and sensorimotor behaviors in a sex-dependent fashion. We have further identified that TSG-6-/- mice display disrupted expression of key regulators of glutamatergic signaling, which we propose are integral to the developmental maturation of neural circuitry underlying these neurobehavioral disturbances. We hypothesize that TSG-6-mediated remodeling of HA in the neonatal brain influences sex-dependent maturation of metabotropic glutamate receptors, glutamate transporters and synaptic spines, which regulate neurotransmission. This proposal will allow us to increase sample size of both males and females to increase statistical power to analyze for sex differences. We will determine key mechanisms by which TSG-6-mediated remodeling of HA in the neonatal brain influences sex- dependent maturation of glutamate receptors, transporters and synaptic spines, which regulate neurotransmission. In aim 1, we will determine whether abnormal expression of glutamatergic signaling regulators in TSG-6-/- brains is sex- and age-dependent. We will analyze the sex- and age-dependent expression of metabotropic glutamate receptors and glutamate transporters including GLT-1, which our preliminary studies found to be dysregulated in TSG-6 null brains. In aim 2, we will determine whether reduction in soma size of TSG-6-/- cortical pyramidal neurons is accompanied by sex-dependent changes in dendritic arborization and spine density in adults. These studies will facilitate our long-term objective to define key cellular and molecular modifications regulated by ECM HA remodeling that influence neuron-astrocyte homeostasis and behavioral outcomes. Our TSG-6-/- animals provide a novel model to address significant gaps in our mechanistic understanding of the sex-dependent regulation of neuronal maturation at critical windows in early brain development that appear to influence later neurobehavioral phenotypes and risk for mental illness in adults.

概括到成年后，早产幸存者患多种形式的严重精神疾病的风险显着增加疾病，包括非情感性精神病、精神分裂症、重度抑郁症和双向情感障碍这项临床前研究计划旨在确定影响性别依赖性因素的作用。生命早期细胞外基质（ECM）介导的机制会增加幸存者患精神疾病的风险因此，我们的建议与战略目标 1.1 和 1.4 一致。我们建议制定 2019-2023 年跨 NIH 女性健康研究战略计划。男性和女性新生儿之间的生物学差异影响与风险增加相关的机制在早产儿大脑发育过程中，我们发现，早产儿幸存者的终生精神疾病。 ECM 的透明质酸 (HA) 主链通过酶 TSG-6（TNFα 刺激）进行重塑基因-6），其显示出峰值活性。我们的初步研究支持 TSG-6 对 ECM HA 的重塑。在敲除小鼠中调节星形胶质细胞的转录成熟，星形胶质细胞是神经元功能不可或缺的一部分。缺乏 TSG-6 活性，成年人在性别依赖性中表现出焦虑和感觉运动行为的改变我们进一步发现 TSG-6-/- 小鼠的关键调节因子的表达受到破坏。谷氨酸信号传导，我们认为它是神经回路发育成熟不可或缺的一部分我们努力探究 TSG-6 介导的 HA 重塑。新生儿大脑影响代谢型谷氨酸受体、谷氨酸的性别依赖性成熟转运蛋白和突触棘，调节神经传递，这一提议将使我们能够增加。我们将增加男性和女性的样本量，以提高分析性别差异的统计能力。确定 TSG-6 介导的新生儿大脑 HA 重塑影响性别的关键机制谷氨酸受体、转运蛋白和突触棘的依赖性成熟，调节在目标1中，我们将确定谷氨酸信号传导是否异常表达。 TSG-6-/- 大脑中的调节因子具有性别和年龄依赖性，我们将分析性别和年龄依赖性表达。代谢型谷氨酸受体和谷氨酸转运蛋白，包括 GLT-1，我们的初步研究在目标 2 中，我们将确定 TSG-6 空脑中是否存在失调。 TSG-6-/- 皮质锥体神经元伴随着树突树枝化和性别依赖性的变化这些研究将有助于我们确定关键细胞和分子的长期目标。 ECM HA 重塑调节的修饰影响神经元-星形胶质细胞稳态和行为我们的 TSG-6-/- 动物提供了一种新颖的模型来解决我们机制中的重大差距。了解早期大脑关键窗口神经成熟的性别依赖性调节发育似乎会影响成人后来的神经行为表型和精神疾病风险。