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.

摘要 自闭症谱系障碍（ASD）是一种常见的神经发育障碍，目前缺乏一个基本的 治疗方法。为了开发一种有效的治疗策略，我们需要了解 ASD是如何建立的。众所周知，怀孕期间感染会增加 后代发展ASD的可能性;因此，我们一直在使用母体免疫激活（MIA） 小鼠ASD模型。使用该模型，我们发现TLR 3配体聚肌苷酸：聚胞苷酸 （Poly（I：C））以及病毒可以通过胎盘并直接激活胎儿边界相关的 巨噬细胞（BAM）在胎儿脑脉络丛（CP）。此外，我们还发现， TLR 3-MIA增加CP中BAM的数量以及增加它们的S100 a8和S100 a9的表达。 S100 a9，它们一起形成称为钙卫蛋白的异二聚体蛋白。由于钙卫蛋白增加 表达与慢性炎症有关，我们推测钙卫蛋白 从CP区的BAM分泌的β-CD可以以自分泌的方式增强炎症， 以旁分泌方式发挥作用，破坏神经祖细胞的分化、迁移和增殖 细胞（NPC）在胎脑的脑室周围区。在本提案中，我们将通过以下方式检验我们的假设： 通过ELISA测量脑脊液中响应于TLR 3-MIA的钙卫蛋白蛋白水平（目的1），和 通过研究钙卫蛋白如何影响我们使用单核细胞的TLR 3-MIA模型中的NPC稳态， RNA-seq（目标2）。如果我们的假设是正确的，这项工作将是朝着开发一种治疗方法迈出的第一步。 通过靶向胎儿脑中的钙卫蛋白治疗ASD的策略。