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：
Peng Jiang
金额：
$ 43.18万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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

来源：
https://reporter.nih.gov/project-details/10752901
关键词：
2019-nCoV Affect Air Pollution Amygdaloid structure Angiolymphoid hyperplasia Animal Model Attention deficit hyperactivity disorder Autoimmune Diseases Bacterial Infections Behavior Behavioral Bipolar Disorder Blood Blood - brain barrier anatomy Brain Brain Diseases Brain region Catalogs Cells Child Chronic Childhood Arthritis Circulation Clinical Research Comparative Study Complex DNA Sequence Alteration DSM-IV Data Development Disease Drug Targeting Etiology Female First Pregnancy Trimester Frequencies Gene Expression Gilles de la Tourette syndrome Human Hypersensitivity Impaired cognition Incidence Individual Infection Injections Interleukin-6 Interneurons Intervention Life Literature Maps Measures Mental Depression Mental disorders Methods Modeling Monitor Mus Neonatal Neurodevelopmental Disorder Neuroglia Neuronal Differentiation Obesity Oligodendroglia Outcome Pathway interactions Performance Physiological Placenta Plasma Pollution Prefrontal Cortex Pregnancy Prevalence Process Production Proliferating Prosencephalon Proteins Protoplasmic Astrocyte Publishing Radial Regulation Rheumatoid Arthritis Risk Risk Factors Schizophrenia Second Pregnancy Trimester Specific qualifier value Spottings Structure Subgroup Surveillance Methods Synapses Temporal Arteritis Therapeutic Time Ventral Striatum Virus Diseases Western Blotting antenatal autism spectrum disorder behavioral phenotyping cytokine epidemiology study fetal fetal blood gliogenesis histogenesis induced pluripotent stem cell inhibitor insight male migration myelination nerve stem cell nestin protein offspring population based postnatal preclinical study prevent progenitor single cell analysis single-cell RNA sequencing subventricular zone synaptogenesis white matter

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.

孕妇感染，过敏，自身免疫性疾病，怀孕期间的肥胖或污染增加后代风险用于发展2-4倍的精神分裂症，ASD，ADHD，Tourette障碍和躁郁症。一个未解决的问题问题是什么正在增强这些疾病的频率。临床研究测量了2-3倍后来患有神经发育障碍的儿童的血液点IL-6血浆水平升高例如ASD。其他研究表明，IL-6是横跨整个的少数细胞因子之一胎盘和血脑屏障以及IL-6的早期胎儿水平升高是必要的，足以足以引起与神经发育障碍相关的几种行为表型。但是，研究是缺乏建立IL-6如何改变胎儿脑发育。这是该提议旨在调查IL-6 影响那些居住在内室内区域内的人类和小鼠次要神经祖细胞 - 一组已被理解的复杂祖细胞。行为和身体结果很高取决于侮辱对大脑的发展时机，这与特定神经直接相关在胎儿生活期间在特定发育阶段进行分裂，迁移和区分的祖细胞。大多数使用动物模型进行ASD和精神分裂症的研究都集中在小鼠与人类妊娠的第12周，径向神经胶质细胞是主要的神经祖细胞。我们的已发布的数据显示，从产后第3天开始，每天两次注射IL-6（与正常水平相比2倍）至6（与人类的妊娠28-34周相关）导致各种表现受到损害行为任务。最近，我们发现IL-6特别影响了一部分的扩散小鼠SVZ神经祖细胞，扰动其增殖和基因表达，从而降低在复杂大脑中实现的几个大脑区域的原生质星形胶质细胞和皮质下少突胶质细胞疾病。这是此应用程序的主要前提是系统地升高的IL-6改变了次生神经祖细胞改变中间神经元和大型创世纪。在这里我们建议生成来自男性和雌性IPSC的人类次要神经祖细胞来确定IL-6如何改变其增殖，规范和基因表达。比较研究将在小鼠SVZ细胞上进行。这些比较研究将使我们能够分类这些人类的二级神经祖细胞。此外，我们将在与IL-6处理的小鼠中进行脂肪图分析，在与IL-6处理的阶段相对应 24周人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完全了解复杂神经发育障碍的组织病理学（例如 ASD。我们专注于在怀孕后期建模感染，对异常神经的起源和大型糖异生将证实IL-6作为预防精神疾病的干预措施的关键目标。