Maternal immune activation remodeling of offspring glycosaminoglycan sulfation patterns during neurodevelopment

神经发育过程中后代糖胺聚糖硫酸化模式的母体免疫激活重塑

• 批准号: 10508305
• 负责人: Kimberly Michele Alonge
• 金额: $ 52.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508305
• 关键词: ATP phosphohydrolase; Acceleration; Adolescent; Adult; Affect; American; Anabolism; Axon; Behavior; Behavioral; Binding; Binding Proteins; Biochemical; Biological; Biology; Bipolar Disorder; Brain; Chemicals; Childhood; Chondroitin Sulfate A; Chondroitin Sulfate C; Chondroitin Sulfates; Clinical Research; Code; Coupled; Cues; Data; Defect; Dermatan Sulfate; Detection; Development; Disease; Elements; Engineering; Event; Exhibits; Exposure to; Extracellular Matrix; Fiber; GAG Gene; Gene Expression; Growth Factor; High Fat Diet; Hippocampus; Hypersensitivity; Immune; Impairment; Interneurons; Intervention; Isomerism; Lactation; Length; Life; Link; Mass Spectrum Analysis; Mediating; Mediator; Mental Depression; Mental Health; Mental disorders; Methodology; Methods; Microglia; Modeling; Motor; Mus; Neurodevelopmental Disorder; Neuroimmune; Patients; Pattern; Polymers; Polysaccharides; Pregnancy; Prevalence; Prevention; Process; Proteins; Regulation; Reporting; Resolution; Risk; Rodent; Schizophrenia; Stimulus; Structure; Sulfate; Techniques; Technology; Zika Virus; autism spectrum disorder; axon growth; axon guidance; axonal pathfinding; biophysical properties; brain volume; cell motility; critical period; cytokine; dermatan sulfate chondroitin sulfate; early childhood; epidemiology study; extracellular; fetal; genetic signature; immune activation; laser capture microdissection; mechanotransduction; migration; mother nutrition; multidisciplinary; nanopore; neurodevelopment; neuropathology; neuropsychiatric disorder; neuropsychiatry; nonhuman primate; novel; offspring; polysulfated glycosaminoglycan; postnatal; postnatal development; preclinical study; prenatal; prevent; regional difference; response; sensor; single molecule; spatiotemporal; synaptogenesis; theories; translational potential

ABSTRACT Maternal immune activation (MIA) during prenatal or postnatal development significantly increases the risk for offspring neurodevelopmental disorders (NDDs) later in life. Growing evidence suggest that regardless of the MIA stimuli (infectious or environmental), offspring exhibit an enhanced risk for lifelong neuropathology defects ranging from reduced brain volume to alterations in neurocircuit organization. The brain extracellular matrix- containing chondroitin and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are key regulators of brain development and can be biochemically altered by neuroimmune responses. Defects in CS/DS-GAG abundance and/or sulfation patterning (4S (CS-A), 2S4S (CS-B/DS), 6S (CS-C), 2S6S (CS-D), 4S6S (CS-E), 0S (CS-O)) result in the manifestation of similar neuropsychiatric behaviors as reported in offspring affected by MIA, but whether and how MIA affects offspring brain matrix is unknown. By employing a novel laser capture microdissection coupled mass spectrometry methodology (LMD-LC-MS/MS), our Preliminary Data provide the first evidence for inter- and intra-regional differences in CS/DS-GAG sulfation pattern differences throughout the developing mouse and non-human primate (NHP) brain. Specifically, the hippocampus exhibits a significant increase in both developmental 6S (CS-C) and 2S6S (CS-D) isomers compared to the cortex, implying that the hippocampus remains developmentally plastic long after the maturation of adjacent regions. Moreover, we show that infectious Zika virus MIA during gestation in NHPs decreases the abundance of the developmental 2S6S (CS-D) axonal growth factor attractant isomer in the hippocampus, suggesting stunted neurocircuit formation after infectious MIA, while the non-infectious maternal high fat diet (mHFD) MIA during lactation in mice decreases the abundance of the developmental 6S (CS-C) plasticity isomer in the hippocampus, suggested accelerated early maturation of hippocampal neurocircuits in response to non-infectious MIA. The implication that both infectious and non-infectious MIA insults influence the spatiotemporal regulation of brain CS/DS-GAG sulfation patterns fits a global interconnecting theory linking a range of MIA insults with changes in offspring brain neurodevelopment through re-coding of CS/DS-GAGs. From these results, we propose to 1) determine how MIA exposure affects spatiotemporal expression of offspring CS/DS-GAGs and link these changes to NDDs later in life, 2) mechanistically investigate how these MIA-induced changes in offspring CS/DS-GAGs influence glycan- protein interactions involved in neurodevelopment, and 3) engineer a state-of-the-art nanopore sequencing technology capable of single-molecule sequencing of biological CS/DS-GAGs to discover glycan-protein binding elements. This multidisciplinary proposal has important translational potential to clarify how MIA exposure leads to neuropsychiatric illness through changes in CS/DS-GAG sulfation patterning during childhood neurodevelopment and provides valuable targets in the prevention and treatment of mental health diseases.

抽象的 产前或产后发育期间产妇免疫激活（MIA）显着增加 后代神经发育障碍（NDDS）在以后的生活中。越来越多的证据表明，不管 MIA刺激（传染性或环境），后代具有终身神经病理缺陷的风险增强 从减少的大脑体积到神经电路组织的变化不等。大脑细胞外基质 含有软骨素和皮肤硫酸盐 - 糖胺聚糖（CS/DS-GAG）是大脑的关键调节剂 开发，可以通过神经免疫反应来改变生化。 CS/DS-GAG丰度缺陷 和/或硫酸化模式（4S（CS-A），2S4S（CS-B/DS），6S（CS-C），2S6S（CS-D），4S6S（CS-E），0S（CS-O）） 导致表现出类似的神经精神行为，如受MIA影响的后代所报告的，但 MIA是否以及如何影响后代脑基质是未知的。通过使用新颖的激光捕获 微分解耦合质谱法（LMD-LC-MS/MS），我们的初步数据提供了 CS/DS-GAG硫酸化模式差异的第一个证据证明了整个CS/DS-GAG硫酸化模式差异 发展小鼠和非人类灵长类动物（NHP）大脑。具体而言，海马表现出显着的 与皮层相比 海马在相邻区域成熟后很长时间保持塑性。而且，我们显示 NHP妊娠期间的传染性寨卡病毒MIA降低了2S6S的丰度 （CS-D）海马中的轴突生长因子吸引剂异构体，表明神经回路的形成发育不良 传染性MIA之后，而小鼠泌乳期间非感染的母体高脂饮食（MHFD）MIA 降低海马中的6s（CS-C）可塑性异构体的丰度，建议 响应非感染的MIA响应海马神经通路的早期成熟。含义 传染性和非感染的MIA侮辱都会影响脑CS/DS-GAG的时空调节 硫化模式符合一种全球互连理论，将一系列MIA侮辱与后代大脑的变化联系起来 通过重新编码CS/DS-GAGS神经发育。从这些结果中，我们提出至1）确定MIA的方式 暴露会影响后代CS/DS-GAG的时空表达，并将这些更改与稍后的NDD联系起来 生命，2）机械学研究这些MIA诱导的后代CS/DS-GAGS的变化如何影响聚糖 涉及神经发育的蛋白质相互作用，3）工程师一种最先进的纳米孔测序 能够对生物CS/DS-GAG进行单分子测序以发现聚糖蛋白结合的技术 元素。该多学科建议具有重要的翻译潜力，以阐明MIA暴露于如何领导 通过改变儿童时期CS/DS-GAG硫酸化模式来使神经精神病疾病 神经发育，并为预防和治疗心理健康疾病提供了宝贵的目标。