Cytokine Regulation of Secondary Neural Progenitors

次级神经祖细胞的细胞因子调节

基本信息

  • 批准号:
    10752901
  • 负责人:
  • 金额:
    $ 43.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-06 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Maternal infection, allergies, autoimmune disease, obesity or pollution during pregnancy increase offspring risk for developing schizophrenia, ASD, ADHD, Tourette disorder and bipolar disorder by 2-4x. An unanswered question is what is enhancing the frequency of these disorders. Clinical studies have measured a 2-3 fold increase in IL-6 plasma levels in blood-spots from children who later develop neurodevelopmental disorders such as ASD. Other studies have shown that IL-6 is one of the few cytokines that is transported across the placenta and blood-brain barrier and that elevated early fetal levels of IL-6 are both necessary and sufficient to cause several behavioral phenotypes associated with neurodevelopmental disorders. However, studies are lacking to establish how IL-6 alters fetal brain development. Thus, this proposal seeks to investigate how IL-6 affects those human and mouse secondary neural progenitors that reside within the inner subventricular zone – a complex set of progenitors that have been understudied. Behavioral and physiological outcomes are highly dependent on the developmental timing of insults to the brain, which are directly related to the particular neural progenitors that are dividing, migrating and differentiating at specific developmental stages during fetal life. The majority of studies using animal models for ASD and schizophrenia have focused on the mouse correlate to the 12th week of human gestation where radial glial cells are the predominant neural progenitors. Our published data show that twice daily injections of IL-6 (that raise levels 2-fold over normal) from postnatal day 3 to 6 (correlating to 28-34 weeks of gestation in humans) leads to compromised performance on a variety of behavioral tasks. Most recently we have found that IL-6 specifically affects the proliferation of a subset of mouse SVZ neural progenitors, perturbing their proliferation and gene expression that reduces production of protoplasmic astrocytes and subcortical oligodendrocytes in several brain regions implicated in complex brain disorders. Thus, the central premise of this application is that systemically elevated IL-6 alters secondary neural progenitors to alter interneuron and macroglial genesis. Here we propose to generate human secondary neural progenitors from male and female iPSCs to determine how IL-6 alters their proliferation, specification and gene expression. Comparative studies will be performed on mouse SVZ cells. These comparative studies will enable us to catalog these human secondary neural progenitors. Furthermore, we will perform fate mapping analyses in mice treated with IL-6 at the stage of development corresponding to 24 weeks of human gestation to analyze histogenesis of the ventral striatum, amygdala and prefrontal cortex to more completely understand the histopathlogical orgins of complex neurodevelopmental disorders such as ASD. Our focus on modeling infections late in pregnancy, on aberrant interneuron genesis and macrogliogenesis will substantiate IL-6 as a key target for intervention to prevent psychiatric disorders.
母体感染、过敏、自身免疫性疾病、肥胖或怀孕期间的污染会增加后代的风险 发展为精神分裂症,ASD,ADHD,Tourette障碍和双相情感障碍的2- 4倍。一个悬而未决的 问题是什么增加了这些疾病的发生率。临床研究表明, 神经发育障碍儿童血斑中IL-6血浆水平升高 如ASD。其他研究表明,IL-6是为数不多的细胞因子之一,它是跨膜转运的。 胎盘和血脑屏障以及早期胎儿IL-6水平的升高都是必要的, 导致几种与神经发育障碍相关的行为表型。然而,研究 缺乏确定IL-6如何改变胎儿大脑发育的研究。因此,本提案旨在研究IL-6如何 影响那些位于脑室下区内部的人类和小鼠次级神经祖细胞 - 一组复杂的祖细胞尚未被充分研究。行为和生理结果是高度 依赖于对大脑的损伤的发育时间,这与特定的神经系统直接相关。 在胎儿生命期间的特定发育阶段分裂、迁移和分化的祖细胞。的 大多数使用ASD和精神分裂症动物模型的研究都集中在小鼠上, 人类妊娠第12周,放射状神经胶质细胞是主要的神经祖细胞。我们 已发表的数据显示,从出生后第3天开始,每天两次注射IL-6(使水平比正常水平提高2倍), 至6周(与人类妊娠28-34周相关)会导致各种性能受损, 行为任务最近,我们发现IL-6特异性地影响一个亚群的增殖, 小鼠SVZ神经祖细胞,干扰其增殖和基因表达,从而减少 涉及复杂脑的几个脑区的原生质星形胶质细胞和皮质下少突胶质细胞 紊乱因此,本申请的中心前提是全身性升高的IL-6改变了 次级神经祖细胞改变中间神经元和大胶质细胞的发生。在这里,我们建议生成 来自雄性和雌性iPSC的人次级神经祖细胞,以确定IL-6如何改变它们的细胞分化。 增殖、特化和基因表达。将对小鼠SVZ细胞进行比较研究。 这些比较研究将使我们能够对这些人类次级神经祖细胞进行分类。此外,委员会认为, 我们将在对应于以下发育阶段的用IL-6处理的小鼠中进行命运作图分析: 24周的人类妊娠,以分析腹侧纹状体、杏仁核和前额叶皮质的组织发生, 更全面地了解复杂神经发育障碍的组织病理学起源, 自闭症我们的重点是在怀孕后期建模感染,异常的中间神经元的发生, 大胶质细胞生成将证实IL-6是预防精神障碍的干预的关键靶标。

项目成果

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Peng Jiang其他文献

Peng Jiang的其他文献

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{{ truncateString('Peng Jiang', 18)}}的其他基金

Cerebral organoid and IPSC derived microglia: Modeling of HIV and methamphetamine co-morbidity
大脑类器官和 IPSC 衍生的小胶质细胞:HIV 和甲基苯丙胺共病模型
  • 批准号:
    10529004
  • 财政年份:
    2022
  • 资助金额:
    $ 43.18万
  • 项目类别:
Cerebral organoid and IPSC derived microglia: Modeling of HIV and methamphetamine co-morbidity
大脑类器官和 IPSC 衍生的小胶质细胞:HIV 和甲基苯丙胺共病模型
  • 批准号:
    10687067
  • 财政年份:
    2022
  • 资助金额:
    $ 43.18万
  • 项目类别:
Understanding Down Syndrome Brain Development Using Human iPSC-Based Mouse Chimeras
使用基于人类 iPSC 的小鼠嵌合体了解唐氏综合症大脑发育
  • 批准号:
    10543474
  • 财政年份:
    2021
  • 资助金额:
    $ 43.18万
  • 项目类别:
A Human iPSC-Based Chimeric Mouse Model of Alzheimers Disease in Down Syndrome
基于人类 iPSC 的唐氏综合症阿尔茨海默病嵌合小鼠模型
  • 批准号:
    10294441
  • 财政年份:
    2021
  • 资助金额:
    $ 43.18万
  • 项目类别:
Understanding Down Syndrome Brain Development Using Human iPSC-Based Mouse Chimeras
使用基于人类 iPSC 的小鼠嵌合体了解唐氏综合症大脑发育
  • 批准号:
    10356933
  • 财政年份:
    2021
  • 资助金额:
    $ 43.18万
  • 项目类别:
Understanding Down Syndrome Brain Development Using Human iPSC-Based Mouse Chimeras
使用基于人类 iPSC 的小鼠嵌合体了解唐氏综合症大脑发育
  • 批准号:
    10179682
  • 财政年份:
    2021
  • 资助金额:
    $ 43.18万
  • 项目类别:
Novel Functions of OLIG2 in Regulating Human Interneuron Production in Health and Disease
OLIG2 在健康和疾病中调节人类中间神经元产生的新功能
  • 批准号:
    9906920
  • 财政年份:
    2018
  • 资助金额:
    $ 43.18万
  • 项目类别:
Novel Functions of OLIG2 in Regulating Human Interneuron Production in Health and Disease
OLIG2 在健康和疾病中调节人类中间神经元产生的新功能
  • 批准号:
    10386789
  • 财政年份:
    2018
  • 资助金额:
    $ 43.18万
  • 项目类别:
Developing an Astroglial Model for Down Syndrome
开发唐氏综合症的星形胶质细胞模型
  • 批准号:
    9299481
  • 财政年份:
    2017
  • 资助金额:
    $ 43.18万
  • 项目类别:
Computational approaches for the analyses of spatial profiling technologies
空间剖析技术分析的计算方法
  • 批准号:
    10487039
  • 财政年份:
  • 资助金额:
    $ 43.18万
  • 项目类别:

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