Project 1: Maternal Immunity in MIA susceptibility

项目 1：MIA 易感性中的母体免疫力

• 批准号: 10214319
• 负责人: JUDY A. VAN DE WATER
• 金额: $ 52.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214319
• 关键词: Address; Adult Children; Affect; Animal Model; Automobile Driving; Behavior; Behavioral; Biological Markers; Brain; Brain Diseases; C57BL/6 Mouse; COVID-19 pandemic; Cells; Corpus striatum structure; Development; Disease; Dopamine; Dose; Early Diagnosis; Early treatment; Epigenetic Process; Etiology; Exhibits; Female; Fever; Future; Goals; Human; Immune; Immune response; Immune signaling; Immunologic Factors; Immunologic Markers; Immunologic Tests; Immunologics; Infection; Inflammatory; Injections; Interleukin-6; Intrinsic factor; Knowledge; Lead; Link; Maternally-Acquired Immunity; Measures; Mediating; Mental disorders; Modeling; Modification; Molecular; Molecular Target; Monkeys; Mus; Neurodevelopmental Disorder; Neuroimmunomodulation; Pathway interactions; Peripheral; Poly C; Poly I-C; Predisposition; Pregnancy; Production; Risk; Risk Factors; Schizophrenia; Serum; Signal Pathway; Signal Transduction; Testing; Time; Viral; Virus Diseases; behavioral outcome; behavioral phenotyping; chemokine; cytokine; endophenotype; experimental study; human disease; immune activation; immunoreactivity; interest; mouse model; neural circuit; neurodevelopment; neuropathology; nonhuman primate; offspring; predictive marker; prevent; resilience; response; sex; success

PROJECT SUMMARY – PROJECT 1 Maternal infection increases susceptibility of offspring to psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). Animal models of maternal immune activation (MIA) support this link, because mid-gestational injection of poly(I:C) induces behavioral and neuropathological abnormalities in adult offspring in domains similar to those affected in SZ. Thus, the poly(I:C) mouse model provides an opportunity to identify the molecular and cellular underpinnings of susceptibility to MIA, which could lead to earlier diagnosis and treatment of brain disease in humans. However, critical gaps in knowledge persist related to two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal infection and (ii) susceptible pregnancies lead to multiple distinct disorders in offspring. We have recently discovered a way to study both of these issues in the MIA mouse model. Results to date have revealed — for the first time — an intrinsic factor, baseline immunoreactivity (BIR) of female mice before pregnancy, that, together with the poly(I:C) dose used to induce MIA, predicts resilience as well susceptibility to neuropathology and aberrant behaviors in offspring. These discoveries provide a unique opportunity to identify immune signatures before and during pregnancy that underlie susceptibility and resilience to MIA, which can be used as biomarkers for susceptible pregnancies. The central goal of this project is to identify the immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced behavioral endophenotypes in offspring. We will address three specific aims: (i) identify immune biomarkers and signaling pathways that underlie the range of BIR in female mice before pregnancy and that correlate with susceptibility and resilience to MIA in offspring, (ii) identify how the progression of the maternal gestational immune response in the mouse model dictates susceptibility or resilience to the effects of MIA in offspring, and (iii) determine if BIR before pregnancy, and the maternal gestational immune response, correlate with susceptibility or resilience to MIA in the non-human primate model. Project 1 directly addresses the central hypothesis and all 3 aims of this Conte Center in a mechanistic manner by identifying immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced neurodevelopmental and behavioral phenotypes in offspring. Results from this project are also essential to the success of the other projects in the Center in revealing the immune signaling pathways that drive susceptibility and resilience to sex-dependent changes in neural circuits (Projects 2, 4 and 5) and neurodevelopmental and behavioral outcomes of offspring (Projects 2-5). Working closely with Project 2, we will also test causality of two immune pathways for MIA-induced changes in striatal DA release and behaviors, developing a pipeline for testing immune pathways (Projects 1, 4) across models (Projects 2, 3, and 5) for their ability to ameliorate the effects of MIA, thereby enhancing the translational relevance of our Center.

项目摘要 – 项目 1 母亲感染会增加后代对精神和神经发育障碍的易感性， 包括精神分裂症（SZ）。母体免疫激活（MIA）动物模型支持这种联系，因为 妊娠中期注射聚（I:C）可诱导成年后代行为和神经病理学异常 与深圳受影响的领域类似。因此，poly(I:C) 小鼠模型提供了一个机会来识别 MIA 易感性的分子和细胞基础，这可能导致早期诊断和 治疗人类脑部疾病。然而，知识方面的重大差距仍然存在，与两个最重要的问题有关 这一人类疾病危险因素的重要方面：(i) 大多数妊娠对孕产妇感染具有抵抗力 (ii) 易感妊娠会导致后代出现多种不同的疾病。我们最近发现了一个 在 MIA 小鼠模型中研究这两个问题的方法。迄今为止的结果首次揭晓 — 雌性小鼠怀孕前的一个内在因素，即基线免疫反应性 (BIR)，与 用于诱导 MIA 的聚 (I:C) 剂量可预测恢复能力以及对神经病理学和异常的易感性 后代的行为。这些发现提供了一个独特的机会来识别免疫特征 以及怀孕期间对 MIA 的易感性和恢复力的基础，这可以用作 MIA 的生物标志物 易感妊娠。该项目的中心目标是确定免疫信号通路 女性在怀孕前和怀孕期间对 MIA 诱发的不同子集具有易感性或恢复力 后代的行为内表型。我们将实现三个具体目标：（i）识别免疫生物标志物 雌性小鼠怀孕前 BIR 范围的信号通路以及与 后代对 MIA 的易感性和恢复力，(ii) 确定母亲妊娠的进展如何 小鼠模型中的免疫反应决定了后代对 MIA 影响的易感性或恢复力，以及 (iii) 确定怀孕前的 BIR 以及母亲妊娠免疫反应是否与 非人类灵长类动物模型中对 MIA 的易感性或恢复力。项目1直接针对中央 通过识别免疫信号以机械方式实现假设和该 Conte 中心的所有 3 个目标 女性在怀孕前和怀孕期间的途径赋予了对不同子集的易感性或恢复力 MIA 诱导后代的神经发育和行为表型。该项目的结果还 对于该中心其他项目的成功至关重要，这些项目揭示了免疫信号通路 提高神经回路对性别依赖性变化的敏感性和恢复力（项目 2、4 和 5） 后代的神经发育和行为结果（项目 2-5）。我们与项目 2 密切合作 还将测试 MIA 诱导的纹状体 DA 释放和行为变化的两条免疫途径的因果关系， 开发跨模型（项目 2、3 和 5）测试免疫途径（项目 1、4）的管道 改善 MIA 影响的能力，从而增强我们中心的转化相关性。