Genetic Dissection of a VIP Link between Immune Dysfunction and Neurodevelopmental Disorders Characterized by Social Deficits

项目1项目概要/摘要 免疫功能障碍已在文献中被广泛报道为促成 以社交缺陷为特征的神经发育障碍，例如，自闭症谱系障碍（ASD）和 精神分裂症从进化的角度来看，数百万年来，人类的行为，特别是 社会性是由两种古老的战斗力量塑造的：病原体和免疫系统。疾病行为 因此，ASD患者对社会交往的回避或回避可以被视为大脑的免疫输入，以逃避 病原体的传播。过去十年的新兴研究开始揭示，免疫输入（例如， 脑膜免疫）确实可以影响神经回路。关键的问题仍然没有答案，包括是否， 功能失调的免疫系统何时以及如何导致以社会性疾病为特征的神经发育障碍 赤字？此外，免疫系统是否可以在治疗上靶向改善社交症状， 自闭症和精神分裂症最近，几项大规模的全基因组关联研究（GWAS）指出， 染色体基因座7q36.6的拷贝数变异（CNV），在精神分裂症中高度表达 和自闭症，所有的微复制（三倍）发生在一个单一的基因：血管活性肠 肽受体2（VIPR 2）。重要的是，VIPR 2配体，血管活性肠肽（VIP）已被发现几乎 使自闭症儿童的新生儿血液中的正常水平增加了两倍。众所周知，VIP/VIPR 2 信号传导调节免疫力并使Th 1/Th 2平衡向有利于Th 2细胞的方向移动。所有这些基因发现 找出长期以来一直在观察的社会缺陷和免疫功能失调之间的联系， 神经发育障碍将这种遗传脆弱性转化为一种机制和病理生理学 我们已经开发了一系列条件性VIPR 2细菌人工染色体（BAC）转基因 VIPR 2 CNV小鼠模型。BAC的条件性设计允许在期望的条件下关闭转基因。 由Cre重组酶控制的时空模式，从而促进受损伤细胞的解剖 人口。遗传性过度激活VIPR 2信号传导导致出生后早期小胶质细胞修剪缺陷， 表现出强烈的社会赤字。因此，我们提出中心假设，过度激活VIP/VIPR 2 T细胞中的信号传导诱发异常免疫转化以破坏社交脑发育和/或社交行为。 行为该假设将在以下具体目标中进行检验：目标1将检验 VIPR 2 CNV在T细胞中引起系统性免疫失衡以破坏出生后早期脑的致病作用 发展这一目标代表了第一个采用化学遗传学方法与设计师受体 设计药物独家激活（DREADD）与CREB-荧光素酶报告基因转基因， 远程控制T细胞类型特异性Gαs GPCR/PKA信号传导，以确定VIPR 2是否驱动Th 2 优先分化足以引起社会缺陷和大脑发育缺陷。我们提出的 在病因学相关的动物模型中进行遗传询问将通过提供 第一次明确的因果关系证据表明，功能失调的免疫力足以和必要的破坏 大脑发育和/或表现出社会行为缺陷。鉴于目前还没有改善病情的疗法 对于自闭症和精神分裂症，我们的研究结果将产生重要的积极影响，因为它们奠定了基础 对于定制治疗的想法（例如，小分子VIPR 2拮抗剂）靶向T细胞免疫， 解决社会症状，这是高度创新的，具有巨大的转化价值。

Project 1 Project Summary/Abstract Immune dysfunction has been extensively reported in the literature as a risk factor contributing to neurodevelopmental disorders characterized by social deficits, e.g., autism spectrum disorder (ASD) and schizophrenia. From an evolutionary perspective, for many millions of years, human behavior, especially sociality, has been shaped by two ancient battling forces: pathogens and the immune system. Sickness behavior or avoidance of social interaction in ASD could thus be viewed as an immune input into the brain to evade the spreading of the pathogens. Emerging research within the last decade starts to reveal that immune inputs (e.g., meningeal immunity) can indeed affect neural circuits. The critical questions remain unanswered include whether, when and how a dysfunctional immunity can cause neurodevelopmental disorders characterized by social deficits? Besides, whether the immune system can be therapeutically targeted to ameliorate social symptoms in autism and schizophrenia? Recently, several large-scale genome-wide association studies (GWAS) pinpointed a Copy Number Variation (CNV) at the chromosomal locus 7q36.6 that is highly represented in schizophrenia and autism, with all of the microduplications (triplications) occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). Importantly, VIPR2 ligand, vasoactive intestinal peptide (VIP) has been found almost tripled the normal level in the neonatal blood of children with autism. It has been well established that VIP/VIPR2 signaling modulates immunity and shifts the Th1/Th2 balance in favor of Th2 cells. All these genetic findings pinpoint a long-sought link between the social deficits and dysfunctional immunity consistently observed in neurodevelopmental disorders. To translate such a genetic vulnerability into a mechanistic and pathophysiologic insight, we have developed a series of conditional VIPR2 Bacterial Artificial Chromosome (BAC) transgenic mouse models of VIPR2 CNV. The conditional design of the BAC allows switching-off the transgene in desired spatial-temporal patterns, controlled by Cre recombinase, thus facilitating dissection of the inflicted cell populations. Genetically over-activated VIPR2 signaling elicits early postnatal microglial pruning deficits and manifests robust social deficits. Therefore, we propose the central hypothesis that over-activated VIP/VIPR2 signaling in T cells elicits abnormal immune transformation to disrupt social brain development and/or social behavior. The hypothesis will be examined in the following specific aims: Aim 1 will examine the potential pathogenic role of VIPR2 CNV in T cells to elicit systemic immune imbalance to disrupt early postnatal brain development. This aim represents the first to employ a chemogenetic approach with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) together with CREB-luciferase reporter transgenesis to remotely control T cell-type-specific Gαs GPCR/PKA signaling to determine whether VIPR2 driven Th2 preferential differentiation is sufficient to elicit social deficits and brain developmental deficits. Our proposed genetic interrogation in an etiology-relevant animal model will shift the paradigm of the field by providing for the first time unequivocal causal evidence to that a dysfunctional immunity is sufficient and necessary to disrupt brain development and/or to manifest social behavioral deficits. Given that there is no disease-modifying therapy for autism and schizophrenia, our results will have an important positive impact because they lay the groundwork to the idea of tailoring of treatments (e.g., small molecule VIPR2 antagonist) targeting T cell immunity for resolution of social symptoms, which is highly innovative, and with tremendous translational value.