Impact of prenatal inflammation on developing human brain

产前炎症对人类大脑发育的影响

• 批准号: 10387980
• 负责人: Alysson R. Muotri
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387980
• 关键词: American; Apoptosis; Appearance; Bacterial Infections; Biological Assay; Birth; Brain; Cells; Cerebrum; Chronic; Coculture Techniques; Data; Detection; Development; Disease; Electroencephalogram; Embryonic Development; Environment; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; Ethnic group; Exposure to; Fetal Development; Gender; Genes; Genetic Transcription; Goals; Hormones; Human; Immune; Immune system; Individual; Infectious Agent; Inflammation; Inflammatory; Intervention; Invaded; Knowledge; Lead; Life; Link; Lipopolysaccharides; Longevity; Measures; Microglia; Modeling; Molecular; Neuraxis; Neurodevelopmental Disorder; Neuroimmune; Neuroimmune system; Neurons; Organoids; Persons; Phenotype; Physiological; Poly I-C; Population; Pregnancy; Premature Birth; Premature Infant; Proteins; RNA; Race; Risk; Role; Sample Size; Sampling; Streptococcus Group B; Subgroup; Synapses; System; Systems Development; Testing; Thyroid Hormones; Time; Toxin; United States; Viral; Virus Diseases; XCL1 gene; Yolk Sac; ZIKV infection; acute infection; autism spectrum disorder; base; brain cell; brain parenchyma; cell type; cohort; developmental disease; disorder risk; ethnic diversity; experience; experimental study; fetal; first responder; gliogenesis; health disparity; healthy pregnancy; immune activation; in utero; in vitro Model; induced pluripotent stem cell; macrophage; multi-electrode arrays; nervous system disorder; neural network; neurodevelopment; neuron development; new therapeutic target; population based; prenatal; prenatal disorder; single-cell RNA sequencing; synaptogenesis; targeted treatment; three-dimensional modeling; tool; transcriptome sequencing; transcriptomics

Project Summary The materno-fetal interface is a crucial environment for a healthy fetal development during pregnancy and delivery. A decrease in maternal trophic factors, such as maternal thyroid hormones or a maternal inflammation/maternal immune activation (MIA) have been linked to an increased risk for neurodevelopmental disorders, such as autism or preterm births. However, there has been no study to date to directly evaluate their impact on human developing brain. To fill this gap of knowledge, we propose to experimentally study the consequences of inflammatory factors on human neurodevelopment using the cerebral organoids co-cultured with microglial cells, a 3D model that mimics the early stages of the human brain development. Microglial cells are immune cells of the central nervous system that are generated in the yolk sac and penetrating the brain parenchyma during a critical time of the embryogenesis coinciding with synaptogenesis and gliogenesis. Given that microglial cells are generated in the periphery, we hypothesized that microglial cells are an important component of the human brain development and most likely the first brain cell type to be exposed and respond to an environmental factor/toxin that can potentially contribute to neurodevelopmental disorders prenatally. Here, we will investigate the impact of maternal inflammation due to bacterial or viral infections on human microglial cells and how that can impact the human developing brain. In addition, given that a person could be exposed to more toxic factors simultaneously or sequentially during that individual’s lifespan or during pregnancy, we will also aim to closely replicate the human experience, by testing the impact of co-exposures to infectious agents and study their synergistic impact on human microglial function and human neurodevelopment. Current studies using iPSCs has been limited sample size and the lack of diversity in the samples that are often derived from donors from a single race/ethnical group. Thus, to have a more inclusive approach, in this proposal, we will use a large cohort of samples from healthy individuals (>50), representative of different races, ethnicities and genders closely mimicking the proportions found in the United States’ population that will provide a better understanding of the health disparities and interventions both in populations and in specific subgroups. Ultimately, our goal is to provide a better understanding of the disease mechanisms involved in maternal inflammation and better targeted therapies from which the majority of the population in the US could benefit from.

项目概要 母婴界面是妊娠期间胎儿健康发育的重要环境 母体营养因子的减少，例如母体甲状腺激素或母体激素的减少。 炎症/母体免疫激活（MIA）与神经发育风险增加有关 然而，迄今为止还没有研究直接评估它们。 为了填补这一知识空白，我们建议进行实验研究。 使用共培养的大脑类器官研究炎症因子对人类神经发育的影响 小胶质细胞是一种模仿人类大脑发育早期阶段的 3D 模型。 是中枢神经系统的免疫细胞，在卵黄囊中产生并穿透大脑 胚胎发生的关键时期的薄壁组织与突触发生和胶质细胞发生同时发生。 由于小胶质细胞是在外周产生的，因此我们认为小胶质细胞是重要的细胞 人类大脑发育的组成部分，很可能是第一个暴露并做出反应的脑细胞类型 可能导致产前神经发育障碍的环境因素/毒素。 在这里，我们将研究细菌或病毒感染引起的母体炎症对人类的影响 小胶质细胞及其如何影响人类发育中的大脑此外，考虑到一个人可能是 在该人的一生或怀孕期间同时或相继接触更多的有毒因素， 我们还将旨在通过测试共同暴露于传染性病毒的影响来密切复制人类的经验 剂并研究它们对人类小胶质细胞功能和人类神经发育的协同影响。 目前使用 iPSC 的研究样本量有限且样本缺乏多样性 通常来自单一种族/族裔群体的捐赠者，因此，在这方面采取更具包容性的方法。 建议，我们将使用来自健康个体（> 50）的大量样本，代表不同种族， 种族和性别与美国人口比例非常相似，这将提供 更好地了解人群和特定亚群体的健康差异和干预措施。 最终，我们的目标是更好地了解孕产妇疾病机制 炎症和更好的靶向治疗，美国大多数人都可以从中受益。