Immune Molecules in Early Postnatal Nervous System Development

产后早期神经系统发育中的免疫分子

• 批准号: 9240678
• 负责人: A Kimberley McAllister
• 金额: $ 39.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240678
• 关键词: Address; Adult; Attention; Axon; Binding; Binding Sites; Biochemistry; Biological Assay; Brain; Calcineurin; Calcium; Cells; Defect; Development; Disease; Environmental Risk Factor; Excitatory Synapse; Exhibits; Family; Future; Genes; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Image; Immune; Immune response; Immune signaling; Immune system; In Vitro; Infection; Interleukin-1 beta; Interleukin-10; Interleukin-6; Laboratories; Link; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Mediating; Mental disorders; Molecular; Nervous system structure; Neurites; Neurodevelopmental Disorder; Neuroimmune; Neurons; Newborn Infant; Pathogenesis; Pathway interactions; Play; Pregnancy; Presynaptic Terminals; Proteins; Publishing; Recruitment Activity; Reporting; Reproducibility; Risk Factors; Role; STAT3 gene; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Structure; Surface; Synapses; Synaptic Vesicles; Therapeutic Intervention; Time; Work; autism spectrum disorder; base; cytokine; density; experimental study; genome wide association study; hippocampal pyramidal neuron; immune activation; immunocytochemistry; in vivo; innovation; insight; knock-down; mouse model; nervous system development; nervous system disorder; neuroimmunology; new therapeutic target; novel; novel therapeutics; offspring; overexpression; patch clamp; postnatal; postsynaptic; presynaptic; presynaptic neurons; public health relevance; spatiotemporal; synaptogenesis; trafficking

 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.

 描述（由申请人提供）：虽然健康的CNS在历史上被认为是“免疫特权”的，但在过去10年中，神经免疫学领域发生了范式转变，这在很大程度上是由于发现了经典免疫分子，包括主要组织相容性复合物I（MHCI）蛋白在发育和成人大脑中表达。MHCI在发育和可塑性中起着广泛的重要作用，包括限制皮层连接的建立和强度。MHCI分子还涉及几种神经发育精神障碍的发病机制，包括精神分裂症（SZ）和自闭症谱系障碍（ASD）。事实上，MHC基因座内的基因显示出迄今为止任何基因中与SZ的最可再现和最显著的全基因组关联，并且MHCI分子也是介导系统性免疫应答对发育中的大脑的影响的有吸引力的候选者，这是SZ和ASD两者的风险因素。然而，尽管有越来越多的证据表明MHCI在大脑中的重要性，但对介导其作用的细胞和分子机制几乎一无所知。该建议的中心目标是：（i）确定介导MHCI负调节突触形成和强度的能力的机制，以及（ii）确定妊娠期间免疫失调如何调节神经元MHCI以改变皮质连接并导致后代疾病。这些目标将通过以下三个具体目标使用免疫细胞化学、生物化学、结构-功能分析、延时成像、新型长期成像测定和全细胞膜片钳记录来实现。(1)明确突触后MHCI在调节皮层连接初步建立中介导功能的细胞和分子机制。(2)明确MHCI分子在轴突和突触前末梢皮层连接建立过程中的作用。(3)确定在发育和疾病过程中作用于MHCI上游以调节其表达和功能的免疫分子和信号通路。该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，从而为它如何有助于神经发育障碍的发病机制提供重要的见解。MHCI上游和下游信号级联的鉴定有可能为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。