Roles of Calprotectin in a mouse model of maternal immune activation

钙卫蛋白在母体免疫激活小鼠模型中的作用

• 批准号: 10593648
• 负责人: Kaoru Saijo
• 金额: $ 23.46万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593648
• 关键词: Acceleration; Affect; Amniotic Fluid; Antibodies; Area; Behavior; Biological Assay; Blood; Brain; CCL2 gene; COVID-19 severity; Cell Line; Cells; Cerebrospinal Fluid; Child; Chronic; Data; Development; Diagnosis; Disease; Embryo; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Exposure to; Female; Fetus; Genetic; Human; IL17 gene; Immune; Immunofluorescence Immunologic; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Innate Immune System; Interleukin-6; Leukocyte L1 Antigen Complex; Ligands; Macrophage; Measures; Mediating; Meninges; Microglia; Modeling; Molecular; Mothers; Mus; Neurodevelopmental Disorder; Pathogenesis; Placenta; Poly I-C; Pregnancy; Probability; Proliferating; Proteins; Reporting; Role; Sepsis; Signal Transduction; Signaling Molecule; Structure of choroid plexus; TLR3 gene; TLR4 gene; Testing; Therapeutic; Time; Toll-like receptors; Ventricular; Virus; Virus Diseases; Wild Type Mouse; Work; adaptive immunity; autism spectrum disorder; autocrine; behavioral phenotyping; brain cell; chronic inflammatory disease; cytokine; effective therapy; fetal; immune activation; immune stimulant; male; maternal immune system; migration; mouse model; nerve stem cell; neuron development; neutralizing antibody; novel therapeutic intervention; offspring; paracrine; pregnant; response; single nucleus RNA-sequencing; single-cell RNA sequencing; stem cell function; stem cell homeostasis; therapeutically effective

Abstract Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that currently lacks a fundamental approach to treatment. To develop an effective therapeutic strategy, we need to understand the molecular mechanism behind how ASD is established. It is known that infection during pregnancy increases the probability of offspring developing ASD; therefore, we have been using a maternal immune activation (MIA) model of ASD in mice. Using this model, we have found that the TLR3 ligand polyinosinic:polycytidylic acid (Poly(I:C)) as well as virus can pass through the placenta and directly activate fetal border-associated macrophages (BAMs) in the choroid plexus (CP) of the fetal brain. Furthermore, we have discovered that TLR3-MIA increases the number of BAMs in the CP as well as increases their expression of S100a8 and S100a9, which together forms a heterodimeric protein called calprotectin. Since increased calprotectin expression is known to associate with chronic inflammatory conditions, we hypothesize that calprotectin secreted from BAMs in the CP region may enhance inflammation in an autocrine manner and may also function in a paracrine manner to disrupt the differentiation, migration, and proliferation of neural progenitor cells (NPCs) in the periventricular area of the fetal brain. In this proposal, we will test our hypothesis by measuring calprotectin protein levels in the cerebrospinal fluid in response to TLR3-MIA by ELISA (Aim 1) and by investigating how calprotectin may influence NPC homeostasis in our TLR3-MIA model using single-nuclei RNA-seq (Aim 2). If our hypothesis is correct, this work will be a first step toward developing a therapeutic strategy for treating ASD by targeting calprotectin in the fetal brain.

抽象的 自闭症谱系障碍（ASD）是一种常见的神经发育障碍，目前缺乏基本 治疗方法。要制定有效的治疗策略，我们需要了解分子 如何建立ASD背后的机制。众所周知，怀孕期间的感染增加了 后代发展ASD的概率；因此，我们一直在使用母体免疫激活（MIA） 小鼠ASD的模型。使用此模型，我们发现TLR3配体聚渗酸：多环酸 （poly（i：c））以及病毒可以通过胎盘并直接激活与胎儿相关的 胎儿脑脉络丛（CP）中的巨噬细胞（BAMS）。此外，我们发现 TLR3-MIA增加了CP中BAM的数量，并增加了其S100A8和 S100A9，共同形成一种称为钙染色素的异二聚体蛋白。自钙染色素增加以来 已知表达与慢性炎症条件相关，我们假设钙骨蛋白 从CP区域中分泌的BAMS可能会以自分泌方式增强炎症，并且也可能 以旁分泌的方式发挥作用，以破坏神经祖细胞的分化，迁移和增殖 细胞（NPC）在胎儿大脑的脑室区域。在此提案中，我们将通过 用ELISA对TLR3-MIA（AIM 1）和 通过调查钙骨蛋白如何使用单核素模型在我们的TLR3-MIA模型中影响NPC稳态 RNA-seq（AIM 2）。如果我们的假设正确，这项工作将是发展治疗的第一步 通过靶向胎儿大脑中的钙染色素来治疗ASD的策略。