Nesprin 1 and 2 in cardiac structure, function, and disease

总结 外核膜蛋白Nesprin 1和2的突变可能参与了 Emery-Dreifuss肌营养不良症（EDMD）样表型，包括心肌病和扩张型 心肌病（DCM）。Nesprins属于一个新发现的血影蛋白重复蛋白家族，由 四名成员。据信，Nesprin 1和2将细胞核锚到肌动蛋白丝，并且普遍存在于细胞中。 表达。为了研究Nesprin 1和2的功能，我们已经产生了以下基因的floxed和全局敲除小鼠： Nesprin 1和2。我们的研究表明，Nesprin 2全基因敲除小鼠是可行的， 基础表型，而超过一半的Nesprin 1全基因敲除（Nesprin 1-/-）小鼠围产期死亡。剩余 Nesprin 1-/-幸存者在三个月大之前体重减轻，运动量减少 容量与其他人的数据一致，我们发现，在双基因敲除小鼠中， Nesprin 1和2。Nesprin 1-/-小鼠和Nesprin 1和2双表达小鼠骨骼肌的组织学分析 敲除小鼠显示非突触核定位异常， 突触核我们还观察到Nesprin 1-/-小鼠显示异常的形状和位置， 心肌细胞核此外，我们观察到SUN 1蛋白水平的上调，SUN 1是一种Nesprin 1结合蛋白， 伴侣和内核膜蛋白，在Nesprin 1-/-心脏样本。这五年的计划是 研究Nesprin 1和2在心脏核位置、核膜结构和心脏功能中的作用。 通过分析突变小鼠及其衍生细胞的功能。我们独特的基因消融能力 Nesprins在小鼠心肌细胞中的作用，结合在心肌细胞中测试分子和生理功能的能力， 整个动物，分离的乳头肌和培养的心肌细胞，将提供新的信息， Nesprins在心脏结构、功能和疾病中的作用。

Summary Mutations in the outer nuclear membrane proteins Nesprin 1 and 2 may be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy (EDMD)-like phenotypes, including cardiomyopathy and dilated cardiomyopathy (DCM). Nesprins belong to a newly discovered family of spectrin-repeat proteins, composed of four members. Nesprin 1 and 2 are believed to anchor nuclei to actin filaments, and are ubiquitously expressed. To investigate functions of Nesprin 1 and 2, we have generated floxed and global knockout mice of both Nesprin 1 and 2. Our studies reveal that Nesprin 2 global knockout mice are viable and have no obvious basal phenotype, whereas over half of Nesprin 1 global knockout (Nesprin 1-/-) mice die perinatally. Remaining Nesprin 1-/- survivors have reduced body weight before three months of age and compromised exercise capacity. Consistent with data from others, we have found 100% perinatal lethality in double knockout mice for Nesprin 1 and 2. Histological analyses of skeletal muscle in Nesprin 1-/- mice and Nesprin 1 and 2 double knockout mice revealed abnormal positioning of non-synaptic nuclei and the disappearance of clusters of synaptic nuclei. We also observed that Nesprin 1-/- mice display abnormal shape and positioning of cardiomyocyte nuclei. In addition, we observed upregulation of protein levels of SUN1, a Nesprin 1 binding partner and an inner nuclear membrane protein, in Nesprin 1-/- heart samples. This 5 year proposal is to investigate the role of Nesprin 1 and 2 in cardiac nuclear position, nuclear membrane structure, and cardiac function by analysis of mutant mice and cells derived from them. Our unique ability to genetically ablate Nesprins in mouse cardiomyocytes, combined with the ability to test molecular and physiological functions in the whole animal, isolated papillary muscles, and cultured cardiomyocytes, will provide novel information as to the function of Nesprins in cardiac structure, function and disease.