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.

摘要 到成年时，早产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、严重抑郁障碍和双相情感障碍 无序。这项临床前研究计划试图定义性别依赖因素对 早期生命细胞外基质(ECM)介导的机制增加幸存者患精神疾病的风险 当他们成熟到成年时，早产的风险。因此，我们的建议符合战略目标1.1。和1.4% 《2019-2023年跨国立卫生研究院妇女健康研究战略计划》。我们建议定义基本的 影响风险增加相关机制的男婴和女婴的生物学差异 用于早产幸存者的终生精神疾病。在早产儿大脑发育过程中，我们发现 细胞外基质的透明质酸(HA)骨架在Tsg-6(肿瘤坏死因子刺激)的作用下发生重塑 基因-6)，显示出最高活性。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，而星形胶质细胞是神经元功能的组成部分。敲除小白鼠 缺乏TSG-6活性的成年人在性依赖的焦虑和感觉运动行为方面表现出变化 时尚。我们进一步发现，TSG-6-/-小鼠的主要调控因子的表达受到干扰。 谷氨酸能信号，我们认为它是神经回路发育成熟所不可或缺的 这些神经行为障碍的潜在原因。我们假设TSG-6介导的HA重塑在 新生儿大脑影响代谢性谷氨酸受体谷氨酸的性别依赖性成熟 转运体和突触脊椎，它们调节神经传递。这项提议将使我们能够增加 男性和女性的样本大小，以增加分析性别差异的统计能力。我们会 确定TSG-6介导的新生儿脑内HA重塑影响性别的关键机制 谷氨酸受体、转运体和突触脊椎的依赖成熟，它们调节 神经传递。在目标1中，我们将确定谷氨酸能信号的异常表达 TSG-6-/-Brains中的调节因子与性别和年龄有关。我们将分析性别和年龄相关的表达 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 在TSG-6基因缺失的脑组织中发现表达失调。在目标2中，我们将确定是否减少 TSG-6-/-皮质锥体神经元伴随着性别依赖性的树突分枝和 成人脊柱密度。这些研究将有助于我们确定关键的细胞和分子的长期目标 细胞外基质HA重塑对神经元-星形胶质细胞动态平衡和行为学的影响 结果。我们的TSG-6-/-动物提供了一种新的模型来解决我们的机制中的重大差距 脑早期临界窗口区神经元成熟的性别依赖性调控 似乎会影响成年后神经行为表型和精神疾病风险的发展。