Coronin 6调控神经肌肉接头乙酰胆碱受体簇集机制研究中国汉族人群系统性红斑狼疮易感基因筛查
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摘要
本毕业论文分为两部分：
1. Coronin6调控神经肌肉接头乙酰胆碱受体簇集机制研究
神经肌肉接头（NMJ）是一类联系神经与肌肉之间的特化突触，负责将运动神经元产生的动作电位传递到肌肉，引起肌肉收缩。乙酰胆碱受体（AChR）簇集于突触后膜，是NMJ发育成熟的最主要标志。现有研究发现，Actin细胞骨架重构对于AChR簇集的形成与维持非常关键。Coronin家族蛋白是一类保守的F-actin结合蛋白，调控actin细胞骨架网络动态变化。本部分研究发现一个新的Coronin蛋白家族成员，Coronin6在NMJ发育过程中参与调控AChR簇集的形成与维持。Coronin6主要表达于成熟骨骼肌，并高度富集于NMJ。在C2C12肌管中，敲减Coronin6抑制agrin诱导AChR簇集形成，并减弱AChR簇集的稳定性。进一步探索Coronin6调控AChR簇集机制，我们发现agrin能诱导Coronin6与AChR-actin细胞骨架形成复合物。这一复合物的形成依赖于Coronin6的Coiled-coil结构域。敲减Coronin6导致AChR簇集与突触后膜细胞骨架关联减弱。此外，Coronin6还能结合于actin，并与F-actin形成共沉淀。缺失UCC结构域（Unique region、Coiled-coil）的Coronin6丧失actin结合能力，并抑制agrin诱导AChR簇集，提示Coronin6介导AChR与actin细胞骨架关联是agrin诱导AChR簇集所必需。综上所述，Coronin6可能通过介导AChR与actin细胞骨架交联而参与调控agrin诱导AChR簇集的形成与维持，在NMJ发育过程中扮演重要角色。
2.中国汉族人群系统性红斑狼疮易感基因筛查
系统性红斑狼疮（SLE）是一种累及全身多个组织器官、慢性复杂的自身免疫性疾病。遗传因素和环境因素共同决定SLE的发生发展。本部分研究采用非标记探针高分辨率熔解曲线的方法鉴定并筛查中国南方汉族人群SLE易感基因（包括BLK、NCF2、PXK、MMDC1、IL-12B以及TNIP1）。最终发现位于BLK基因上的SNPrs13277113、rs4840568以及位于IL-12B基因上的SNP rs6887695与汉族人群SLE的发病风险具有显著性相关。
Two projects are included in this thesis.
Project I: Coronin6regulates AChR clustering at the neuromuscular junction
Neuromuscular junction (NMJ) is a type of chemical synapse between motor neuronand skeletal muscle. Acetylcholine receptors (AChR) clustering at postsynaptic membraneis the predominant feature of mature NMJ. Re-organization of postsynaptic cytoskeletonsystem is critical for formation and maintenance of AChR clusters. Coronins, a proteinfamily with high F-actin binding activity, regulates actin dynamics in many types of cells.In present work, we identify Coronin6, a novel member of Coronin family, regulates AChRclustering at postsynaptic membrane. Coronin6is predominately expressed in skeletalmuscle and highly concentrated at the NMJ. Knockdown of Coronin6not only inhibitsagrin-induced AChR clustering but also accelerates the dispersal of AChR clusters afteragrin withdrawal. To explore the underlying mechanism on how Coronin6regulates AChRclustering, we find that Coronin6is associated with Actin-AChR complex upon agrinstimulus. Coiled-coil domain of Coronin6is required for this association. Knockdown ofCoronin6reduces the linkage between AChR clusters and cytoskeleton system asindicating by reduction of p-Try-AChRβ level and loss of the AChR extractibility inCoronin6silenced-myotubes. Moreover, Coronin6is able to bind with F-actin. The uniqueregion and coiled-coil domain (UCC) of Coronin6are required for its actin binding activity.Overexpression of Coronin6with UCC domain deletion inhibits agrin-induced AChRclustering, suggesting that actin binding activity of Coronin6is required for agrin-inducedAChR clustering. Taken together, our work indicates that Coronin6regulates postsynapticAChR clustering via mediating the linkage between AChR cluster and actin cytoskeletonsystem.
Project II: Identification of SLE susceptive genes in Chinese Han population
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affectingmultiple organs. Both genetic factors and environmental influences are contributed to thedevelopment and progression of SLE. In this work, we screened several SLE susceptive genes including BLK, NCF2, PXK, MAMDC1, IL-12B and TNIP1in Chinese Hanpopulation by high resolution melting curve with unlabeled probe and finally find that bothSNPs (rs13277113and rs4840568) on the BLK gene and SNP rs6887695on IL-12B geneare associated with the disease risks of SLE in Chinese Han population, respectively.
1. Coronin6调控神经肌肉接头乙酰胆碱受体簇集机制研究
神经肌肉接头（NMJ）是一类联系神经与肌肉之间的特化突触，负责将运动神经元产生的动作电位传递到肌肉，引起肌肉收缩。乙酰胆碱受体（AChR）簇集于突触后膜，是NMJ发育成熟的最主要标志。现有研究发现，Actin细胞骨架重构对于AChR簇集的形成与维持非常关键。Coronin家族蛋白是一类保守的F-actin结合蛋白，调控actin细胞骨架网络动态变化。本部分研究发现一个新的Coronin蛋白家族成员，Coronin6在NMJ发育过程中参与调控AChR簇集的形成与维持。Coronin6主要表达于成熟骨骼肌，并高度富集于NMJ。在C2C12肌管中，敲减Coronin6抑制agrin诱导AChR簇集形成，并减弱AChR簇集的稳定性。进一步探索Coronin6调控AChR簇集机制，我们发现agrin能诱导Coronin6与AChR-actin细胞骨架形成复合物。这一复合物的形成依赖于Coronin6的Coiled-coil结构域。敲减Coronin6导致AChR簇集与突触后膜细胞骨架关联减弱。此外，Coronin6还能结合于actin，并与F-actin形成共沉淀。缺失UCC结构域（Unique region、Coiled-coil）的Coronin6丧失actin结合能力，并抑制agrin诱导AChR簇集，提示Coronin6介导AChR与actin细胞骨架关联是agrin诱导AChR簇集所必需。综上所述，Coronin6可能通过介导AChR与actin细胞骨架交联而参与调控agrin诱导AChR簇集的形成与维持，在NMJ发育过程中扮演重要角色。
2.中国汉族人群系统性红斑狼疮易感基因筛查
系统性红斑狼疮（SLE）是一种累及全身多个组织器官、慢性复杂的自身免疫性疾病。遗传因素和环境因素共同决定SLE的发生发展。本部分研究采用非标记探针高分辨率熔解曲线的方法鉴定并筛查中国南方汉族人群SLE易感基因（包括BLK、NCF2、PXK、MMDC1、IL-12B以及TNIP1）。最终发现位于BLK基因上的SNPrs13277113、rs4840568以及位于IL-12B基因上的SNP rs6887695与汉族人群SLE的发病风险具有显著性相关。
Two projects are included in this thesis.
Project I: Coronin6regulates AChR clustering at the neuromuscular junction
Neuromuscular junction (NMJ) is a type of chemical synapse between motor neuronand skeletal muscle. Acetylcholine receptors (AChR) clustering at postsynaptic membraneis the predominant feature of mature NMJ. Re-organization of postsynaptic cytoskeletonsystem is critical for formation and maintenance of AChR clusters. Coronins, a proteinfamily with high F-actin binding activity, regulates actin dynamics in many types of cells.In present work, we identify Coronin6, a novel member of Coronin family, regulates AChRclustering at postsynaptic membrane. Coronin6is predominately expressed in skeletalmuscle and highly concentrated at the NMJ. Knockdown of Coronin6not only inhibitsagrin-induced AChR clustering but also accelerates the dispersal of AChR clusters afteragrin withdrawal. To explore the underlying mechanism on how Coronin6regulates AChRclustering, we find that Coronin6is associated with Actin-AChR complex upon agrinstimulus. Coiled-coil domain of Coronin6is required for this association. Knockdown ofCoronin6reduces the linkage between AChR clusters and cytoskeleton system asindicating by reduction of p-Try-AChRβ level and loss of the AChR extractibility inCoronin6silenced-myotubes. Moreover, Coronin6is able to bind with F-actin. The uniqueregion and coiled-coil domain (UCC) of Coronin6are required for its actin binding activity.Overexpression of Coronin6with UCC domain deletion inhibits agrin-induced AChRclustering, suggesting that actin binding activity of Coronin6is required for agrin-inducedAChR clustering. Taken together, our work indicates that Coronin6regulates postsynapticAChR clustering via mediating the linkage between AChR cluster and actin cytoskeletonsystem.
Project II: Identification of SLE susceptive genes in Chinese Han population
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affectingmultiple organs. Both genetic factors and environmental influences are contributed to thedevelopment and progression of SLE. In this work, we screened several SLE susceptive genes including BLK, NCF2, PXK, MAMDC1, IL-12B and TNIP1in Chinese Hanpopulation by high resolution melting curve with unlabeled probe and finally find that bothSNPs (rs13277113and rs4840568) on the BLK gene and SNP rs6887695on IL-12B geneare associated with the disease risks of SLE in Chinese Han population, respectively.
引文
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