Sex-Biased Mitochondrial Alterations Underlying Male Susceptibility to Neurodevelopmental Disorders

男性对神经发育障碍易感性的性别偏见线粒体改变

• 批准号: 10374457
• 负责人: Evan Andrew Bordt
• 金额: $ 2.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374457
• 关键词: ASD patient; Adolescent; Affect; Autopsy; Behavior; Behavioral; Biological Assay; Biology; Birth; Brain; Brain region; Cells; Child; Collection; Communication; Complex; DNA; DNA Methylation; DNA Sequence; DNA Sequence Alteration; DNMT3a; Development; Diagnosis; Disease; Disease susceptibility; Electron Transport; Epigenetic Process; Estradiol; Exhibits; Female; Functional disorder; Gene Proteins; Genes; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Heterogeneity; Hormones; Immune; Immunohistochemistry; Immunoprecipitation; Incidence; Individual; Injections; Life; Lipopolysaccharides; Masculine; Mediating; Methyltransferase; Microglia; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morphology; Mus; Mutation; Nature; Nervous System Physiology; Neuraxis; Neurodevelopmental Disorder; Neuroimmune; Neurologic; Outcome; Oxygen Consumption; Patients; Pattern; Perinatal; Physiology; Play; Positioning Attribute; Predisposition; Prefrontal Cortex; Prevalence; Process; Protein Isoforms; Reporting; Research; Respiratory physiology; Role; Saline; Sex Bias; Sex Differences; Social Behavior; Social Interaction; Stimulus; Testing; Translating; United States; autism spectrum disorder; brain cell; causal variant; cell type; critical period; early onset; enzyme activity; epigenetic regulation; experimental study; genetic regulatory protein; immune activation; impaired brain development; male; male sex hormones; mitochondrial dysfunction; neural circuit; neurodevelopment; neuroinflammation; neuropsychiatry; next generation; novel; postnatal; preference; protein expression; relating to nervous system; repetitive behavior; response; sex; social; social communication; subcutaneous; transcriptome; transcriptome sequencing; young adult

PROJECT SUMMARY Autism Spectrum Disorders (ASD) are a collection of complex neurodevelopmental disorders characterized by repetitive behaviors and alterations in social interaction and communication that currently affect 1 in 68 children in the United States. Although it is clear that ASD prevalence is biased towards males (~4:1 male to female ratio), the mechanisms behind this male susceptibility remain elusive. While ASDs are quite heterogenous, evidence suggests a role for neuroinflammation in the development of these neurological abnormalities. Microglia, the resident immune cells of the brain, are key regulators of the neural response to immune activation and developmental organization of neural circuits, uniquely positioning them to translate early-life challenges into neural outcomes. Additionally, emerging evidence suggests that mitochondrial dysfunction plays an important role in neuropsychiatric/neurodevelopmental disorders such as ASD, and that inhibition of mitochondrial function may be critical in the processes of microglial activation. The emerging understanding of sex differences in mitochondrial and microglial physiology suggest that further study into their potential roles in the development of neurodevelopmental disorders such as ASD are warranted. To that end, I will first characterize the effect of early-life immune challenge (an established model for ASD in mice that presents with a strong sex bias) on mitochondrial gene/protein levels and functions. Building upon this, I will then assess how an early-life immune stimulus affects epigenetic regulation of mitochondrial DNA in males and females. Finally, I will ask what could be occurring during early development that may mediate these early- onset sex differences. There is a surge in gonadal hormone levels that occurs only in males during a ‘critical period’ of days surrounding birth that is responsible for masculinizing male brains. Injections of these hormones into females during this ‘critical period’ has been shown to ‘masculinize’ their brains to a male-like state. Using this model, I will determine if male sex hormones present during a critical period surrounding birth (‘masculinizing’ female mice) will impart susceptibility to subsequent immune challenge. I expect this project to result in several novel implications by bridging three bodies of research that are only beginning to collaborate: (i) the role of mitochondrial biology in neurodevelopment and disease, (ii) the role of neuroimmune dysfunction and microglial function in neurodevelopment and disease, and (iii) the striking differences in male and female responses to pathophysiological insults.

项目摘要 自闭症谱系障碍（ASD）是一组复杂的神经发育障碍 以重复的行为和社会互动和交流的变化为特征， 在美国，每68名儿童中就有1名受到影响。虽然ASD的患病率明显偏向于男性， （~4：1的男女比例），这种男性易感性背后的机制仍然难以捉摸。虽然ASD 相当异质性，证据表明神经炎症在这些神经系统疾病的发展中起作用。 异常小胶质细胞，大脑的常驻免疫细胞，是神经反应的关键调节器， 免疫激活和神经回路的发育组织，独特地定位它们， 早期生活的挑战转化为神经结果。此外，新出现的证据表明， 功能障碍在神经精神/神经发育障碍如ASD中起重要作用， 线粒体功能的抑制在小胶质细胞活化过程中可能是关键的。新兴 对线粒体和小胶质细胞生理学的性别差异的理解表明，进一步研究它们的 在神经发育障碍如ASD的发展中的潜在作用是有保证的。为此我 将首先描述早期免疫攻击的效果（一种建立的小鼠ASD模型， 存在强烈的性别偏见）对线粒体基因/蛋白质水平和功能的影响。在此基础上，我 然后评估生命早期的免疫刺激如何影响男性线粒体DNA的表观遗传调控， 女性最后，我会问在早期发育过程中可能发生什么，可能介导这些早期- 发病性别差异。只有在“关键时期”，男性才会出现性腺激素水平的激增。 出生前后的一段时间，负责使男性大脑男性化。注射这些 在这一“关键时期”，向女性注射激素， 状态利用这个模型，我将确定男性性激素是否存在于出生的关键时期 （“雄性化”雌性小鼠）将赋予对随后的免疫攻击的易感性。我希望这个项目 通过连接三个刚刚开始合作的研究机构，产生了几个新的影响： (i)线粒体生物学在神经发育和疾病中的作用，（ii）神经免疫功能障碍的作用 和小胶质细胞在神经发育和疾病中的功能，以及（iii）男性和女性的显着差异 对病理生理损伤的反应。