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

基本信息

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
项目类别：
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

项目摘要

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，目前缺乏基本的治疗方法治疗方法。为了制定有效的治疗策略，我们需要了解分子机制 ASD 建立背后的机制。众所周知，怀孕期间的感染会增加后代患自闭症谱系障碍的概率；因此，我们一直在使用母体免疫激活（MIA）小鼠 ASD 模型。利用该模型，我们发现TLR3配体聚肌苷酸：聚胞苷酸 (Poly(I:C))以及病毒可以穿过胎盘并直接激活胎儿边界相关的胎儿大脑脉络丛 (CP) 中的巨噬细胞 (BAM)。此外，我们还发现 TLR3-MIA 增加了 CP 中 BAM 的数量并增加了 S100a8 和 S100a8 的表达 S100a9，它们一起形成一种称为钙卫蛋白的异二聚体蛋白。由于钙卫蛋白增加已知表达与慢性炎症状况相关，我们假设钙卫蛋白 CP 区 BAM 分泌的 BAM 可能以自分泌方式增强炎症，也可能以旁分泌方式发挥作用，破坏神经祖细胞的分化、迁移和增殖胎儿大脑脑室周围区域的细胞（NPC）。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 TLR3-MIA 的钙卫蛋白水平（目标 1）和通过使用单核研究钙卫蛋白如何影响我们的 TLR3-MIA 模型中的 NPC 稳态 RNA 测序（目标 2）。如果我们的假设是正确的，这项工作将是开发治疗方法的第一步通过靶向胎儿大脑中的钙卫蛋白来治疗 ASD 的策略。