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.

概括成年后，早产的存活情况大大增加了几种严重精神的风险疾病，包括无影响的精神病，精神分裂症，重度抑郁症和双相情感紊乱。这项临床前研究提案旨在定义影响性别依赖性因素的作用早期生命额外的细胞基质（ECM）介导的机制，导致幸存者的精神疾病风险他们成熟到成年时过早出生。因此，我们的建议与战略目标1.1保持一致。和1.4 2019-2023妇女健康研究的Trans-NIH战略计划。我们建议定义基本男性和女性新生儿之间影响与增强风险相关的机制的生物学差异在早产中终身精神疾病。在早产新生儿大脑发育期间，我们发现 ECM的透明质酸（HA）主链通过酶TSG-6进行重塑（TNF刺激 Gene-6），显示峰活动。我们的初步研究支持TSG-6重塑ECM HA 调节星形胶质细胞的转录成熟，这是神经元功能不可或缺的。在淘汰那个老鼠缺乏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时尚。我们进一步确定TSG-6 - / - 小鼠显示残疾人表达的关键调节器的表达谷氨酸能信号传导，我们建议的是神经回路发展成熟不可或缺的一部分这些神经行为灾难的基础。我们假设TSG-6介导的HA重塑新生儿大脑会影响代谢性谷氨酸受体的性别依赖性成熟，谷氨酸转运蛋白和突触刺，调节神经传递。该建议将使我们能够增加男性和女性的样本大小，以增加统计能力以分析性别差异。我们将确定TSG-6介导的HA在新生儿大脑中重塑的关键机制会影响性别调节谷氨酸受体，转运蛋白和突触棘的依赖性成熟神经传递。在AIM 1中，我们将确定谷氨酸能信号的异常表达是否 TSG-6 - / - 大脑中的调节剂是性别和年龄依赖性的。我们将分析性别和年龄依赖性表达包括GLT-1在内的代谢型谷氨酸受体和谷氨酸转运蛋白的作品，我们的初步研究发现在TSG-6无效的大脑中失调。在AIM 2中，我们将确定SOMA大小的降低是否减少 TSG-6 - / - 皮质锥体神经元伴随着树突状树皮化和性别依赖性变化成人的脊柱密度。这些研究将促进我们的长期目标定义关键细胞和分子通过ECM HA重塑调节的修饰，影响神经元 - 腹部稳态和行为结果。我们的TSG-6 - / - 动物提供了一种新型模型，以解决我们的机械差距了解早期大脑关键窗口中神经元成熟的性别依赖性调节似乎影响后来神经行为的表型和成人精神疾病的风险的发展。