Role of the Sez6 family in synapse pruning

Sez6家族在突触修剪中的作用

基本信息

批准号：
9891120
负责人：
JENNETTA W HAMMOND
金额：
$ 19.25万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891120
关键词：
16p11.2 Binding Biological Assay Brain Cell membrane Cells Complement Complement 1q Complement Activation Data Deposition Development Disease Dorsal Family Future Gene Family Genes Goals Homer 1 Immune Immune System Diseases In Vitro Infection Inflammatory Knock-out Knockout Mice Lateral Geniculate Body Mediating Microglia Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Pathologic Pathway interactions Phenotype Predisposition Property Protein Family Proteins Regulation Role Schizophrenia Self-Direction Serum Structure Susceptibility Gene Synapses Tertiary Protein Structure Testing Thalamic structure TimeLine Tissues Translating Visual system structure Work autism spectrum disorder cognitive function complement pathway complement system critical period experimental study fighting genetic regulatory protein in vitro Model in vivo insight member mouse model neural circuit neuroinflammation novel overexpression prevent protein function relating to nervous system repaired retinogeniculate sample fixation synaptic function synaptic pruning therapy design

项目摘要

Complement promotes synaptic pruning by glia in order to refine neural circuits during development, but may also pathologically destroy mature, essential synapses in the context of neuroinflammation. Immune dysfunction and an imbalance in synaptic pruning have been implicated in autism spectrum disorder (ASD), and recent studies suggest that dysregulation of complement may be connected. The central hypothesis to be tested in this application is that the Sez6 gene family, whose members have been identified as ASD susceptibility genes, are novel, synaptically localized, complement regulators that are required to prevent aberrant synaptic pruning related to ASD. In Aim 1, we will define the complement regulatory properties of Sez6, Sez6L, and Sez6L2 using standard complement assays. We will then investigate whether the Sez6 family can prevent complement deposition at synapses in vitro. In Aim 2, we will use the 16p11.2 deletion mouse model of autism, in which Sez6L2 is lost along with other genes, to determine if enhanced complement dependent synapse pruning occurs at retinogeniculate synapses in the visual system. A Sez6L2 knockout will also be tested in order to validate findings and confirm the importance of SezL2 to the 16p11.2 phenotype. In aggregate, we expect the data obtained from these experiments to advance our understanding of the role of Sez6 proteins in mechanisms underlying complement-mediated synapse elimination during development that may explain how this gene family contributes susceptibility to ASD.

补体促进神经胶质细胞的突触修剪，以改善神经回路发育，但也可能病理性地破坏成熟的、重要的突触神经炎症。免疫功能障碍和突触修剪不平衡已被与自闭症谱系障碍（ASD）有关，最近的研究表明，失调补体可以连接。本申请要测试的中心假设是 Sez6基因家族，其成员已被鉴定为ASD易感基因，是防止异常所需的新型突触局部补体调节因子与 ASD 相关的突触修剪。在目标 1 中，我们将定义补体监管属性使用标准补体测定法检测 Sez6、Sez6L 和 Sez6L2。我们随后将进行调查 Sez6家族是否可以在体外阻止补体沉积在突触处。在目标 2 中，我们将使用 16p11.2 缺失自闭症小鼠模型，其中 Sez6L2 与其他基因，以确定增强的补体依赖性突触修剪是否发生在视觉系统中的视网膜突触。 Sez6L2 淘汰赛也将按顺序进行测试验证研究结果并确认 SezL2 对 16p11.2 表型的重要性。在总的来说，我们希望从这些实验中获得的数据能够加深我们的理解 Sez6 蛋白在补体介导的突触机制中的作用发育过程中的消除可能解释该基因家族如何影响易感性到自闭症谱系障碍。