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

• 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
• 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' 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

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.

总结 到成年时，早产的幸存者患几种严重精神疾病的风险显著增加。 疾病，包括非情感性精神病、精神分裂症、重度抑郁症和双相情感性精神病 disorder.这项临床前研究计划旨在确定性别依赖因素的作用， 生命早期细胞外基质（ECM）介导的机制，有助于幸存者患精神疾病的风险 早产的风险。因此，我们的提议与战略目标1.1是一致的。和1.4的 2019-2023年跨NIH妇女健康研究战略计划。我们建议定义基本 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 早产儿幸存者的终身精神疾病。在早产新生儿大脑发育过程中，我们发现， ECM的透明质酸（HA）骨架通过酶TSG-6（TNF α刺激的 基因-6），其显示峰值活性。我们的初步研究支持TSG-6对ECM HA的重塑 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的组成部分。在敲除小鼠中， 缺乏TSG-6活性，成年人表现出焦虑和感觉运动行为的改变， 时尚.我们进一步鉴定了TSG-6-/-小鼠表现出干扰的关键调节因子表达， 神经元能信号，我们认为是神经回路发育成熟的组成部分 这些神经行为紊乱的根本原因我们推测，TSG-6介导的HA重塑可能是由于TSG-6介导的HA重塑。 新生儿脑影响代谢型谷氨酸受体的性别依赖性成熟， 转运蛋白和突触棘，调节神经传递。这项提案将使我们能够增加 男性和女性的样本量，以增加分析性别差异的统计功效。我们将 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， 神经传递在目的1中，我们将确定是否有异常表达的多巴胺能信号转导， TSG-6-/-大脑中的调节因子是性别和年龄依赖的。我们将分析性别和年龄依赖的表达， 代谢型谷氨酸受体和谷氨酸转运体，包括GLT-1，我们的初步研究， 发现在TSG-6无效脑中失调。在目标2中，我们将确定是否减少索马大小， TSG-6-/-皮质锥体神经元伴随着树突分支的性别依赖性变化， 成年人的脊椎密度这些研究将有助于我们的长期目标，以确定关键的细胞和分子 由ECM HA重塑调节的修饰影响神经元-星形胶质细胞的稳态和行为 结果。我们的TSG-6-/-动物提供了一种新的模型，以解决我们的机制中的重大差距。 对早期脑中神经元成熟关键窗口期的性别依赖性调节的理解 发展，似乎影响以后的神经行为表型和成年人的精神疾病的风险。