Immune Molecules in Early Postnatal Nervous System Development

 描述(申请人提供)：尽管健康的中枢神经系统在历史上被认为是“免疫特权”，但神经免疫学领域的范式在过去10年中已经发生了转变，这在很大程度上是因为发现包括主要组织相容性复合体I(MHCI)蛋白在内的经典免疫分子在发育中的和成人的大脑中表达。MHCI在发育和可塑性中发挥着广泛的重要作用，包括限制皮质连接的建立和强度。MHCI分子也与几种神经发育精神障碍的发病机制有关，包括精神分裂症(SZ)和自闭症谱系障碍(ASD)。事实上，在迄今为止的所有基因中，MHC基因座内的基因显示出与SZ最具重复性和显著的全基因组关联，MHCI分子也是调节发育中的大脑的系统性免疫反应影响的有吸引力的候选分子，这是SZ和ASD的风险因素。然而，尽管有越来越多的证据表明MHCI在大脑中的重要性，但几乎对其影响的细胞和分子机制知之甚少。这项建议的中心目标是：(I)确定介导MHCI负面调节突触形成和强度的机制，以及(Ii)确定神经元MHCI如何在妊娠期间受到免疫失调的调节，从而改变皮质连接并导致子代疾病。这些目标将通过免疫细胞化学、生物化学、结构-功能分析、时间推移成像、一种新的长期成像分析和全细胞膜片钳记录来实现，通过以下三个具体目标。(1)明确介导突触后MHCI调节皮质连接初始建立的细胞和分子机制。(2)确定MHCI分子在皮层连接建立过程中轴突和突触前终末的功能。(3)识别在MHCI上游起作用的免疫分子和信号通路，以调节其在发育和疾病中的表达和功能。这个项目的结果将增加我们对MHCI如何调节大脑发育和功能的理解，从而为它如何可能有助于神经发育障碍的发病机制提供关键的见解。识别MHCI上游和下游的信号级联可能为ASD和SZ的分子机制提供新的见解，并揭示旨在挽救这些疾病中突触缺陷的治疗干预的创新和意想不到的新靶点。

 DESCRIPTION (provided by applicant): Although the healthy CNS was historically assumed to be "immune-privileged," a paradigm shift in the field of neuroimmunology has occurred in the last 10 years due in large part to the discovery that classical immune molecules, including major histocompatibility complex I (MHCI) proteins are expressed in the developing and adult brain. MHCI plays a wide range of important roles in development and plasticity, including limiting the establishment and strength of cortical connections. MHCI molecules have also been implicated in the pathogenesis of several neurodevelopmental psychiatric disorders, including schizophrenia (SZ) and autism spectrum disorders (ASD). In fact, genes within the MHC locus show the most reproducible and significant genome-wide association with SZ of any genes to date and MHCI molecules are also attractive candidates for mediating the effects of a systemic immune response on the developing brain, which is a risk factor for both SZ and ASD. However, despite this accumulating evidence for the importance of MHCI in the brain, almost nothing is known about the cellular and molecular mechanisms that mediate its effects. The central goals of this proposal are to: (i) determine the mechanisms that mediate the ability of MHCI to negatively regulate synapse formation and strength and (ii) identify how neuronal MHCI is regulated by immune dysregulation during gestation to alter cortical connections and cause disease in offspring. These goals will be accomplished using immunocytochemistry, biochemistry, structure-function analysis, time-lapse imaging, a novel long-term imaging assay, and whole-cell patch-clamp recording, through the following three specific Aims. (1) To identify the cellular and molecular mechanisms that mediate the function of postsynaptic MHCI in regulating the initial establishment of cortical connections. (2) To determine the function for MHCI molecules in the axon and presynaptic terminal during the establishment of cortical connections. (3) To identify the immune molecules and signaling pathways that act upstream of MHCI to regulate its expression and function during development and in disease. Results from this project will increase our understanding of how MHCI regulates brain development and function, thereby providing critical insight into how it might contribute to the pathogenesis of neurodevelopmental disorders. Identification of the signaling cascades upstream and downstream of MHCI has the potential to provide fresh insight into the molecular mechanisms underlying ASD and SZ and to reveal innovative and unexpected new targets for therapeutic intervention aimed at rescuing synaptic defects in these disorders.