Project 1: Maternal Immunity in MIA susceptibility

项目 1：MIA 易感性中的母体免疫力

• 批准号: 10592304
• 负责人: JUDY A. VAN DE WATER
• 金额: $ 46.26万
• 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/10592304
• 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 I-C; Predisposition; Pregnancy; Production; Risk; Risk Factors; Schizophrenia; Serum; Signal Pathway; Signal Transduction; Testing; Time; Viral; Virus Diseases; behavioral outcome; behavioral phenotyping; biomarker identification; 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 孕产妇感染增加了后代对精神病和神经发育障碍的敏感性， 包括精神分裂症（SZ）。母体免疫激活（MIA）的动物模型支持此联系，因为 妊娠注射poly（i：c）诱导成人后代的行为和神经病理异常 在类似于SZ中的域类似的域中。那就是poly（i：c）鼠标模型提供了一个机会来识别 对MIA敏感性的分子和细胞基础，这可能导致较早的诊断和 治疗人类脑疾病。但是，知识的关键差距持续与最大的两个有关 这种危险因素的重要方面是人类疾病：（i）大多数怀孕对孕产妇感染有弹性 （ii）敏感的怀孕导致后代多种不同的疾病。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示了 - 固有因素，雌性小鼠怀孕前的基线免疫反应性（BIR）， poly（i：c）用于诱导MIA的剂量，预测弹性以及对神经病理学和异常的敏感性 后代的行为。这些发现为识别免疫特征提供了独特的机会 在怀孕期间，这是对MIA的敏感性和韧性的基础，可以用作生物标志物的 敏感的怀孕。该项目的核心目标是识别中的免疫信号通路 在怀孕前后 后代的行为内表型。我们将解决三个具体目标：（i）确定免疫生物标志物 以及怀孕前女性小鼠BIR范围的信号通路，与 （ii）确定母体妊娠的进展如何 小鼠模型中的免疫反应决定了MIA在后代的影响的敏感性或韧性，并且 （iii）确定BIR是否在怀孕前和母体妊娠免疫反应，与 在非人类私人模型中对MIA的敏感性或对MIA的韧性。项目1直接解决中央 假设和该孔戴中心的所有3个目标都通过识别免疫信号传导 在怀孕之前和怀孕期间，女性的途径是会议的敏感性或对不同子集的抗韧性 MIA引起的后代神经发育和行为表型。该项目的结果也是 对中心其他项目在揭示免疫信号通路方面的成功至关重要 推动对神经回路的性别依赖性变化的敏感性和韧性（项目2、4和5）和 后代的神经发育和行为结果（项目2-5）。与项目2紧密合作，我们 还将测试两种免疫途径的偶然性，以实现MIA诱导的纹状体DA释放和行为变化， 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的影响，从而增强我们中心的翻译相关性。