Functional characterization of newly identified inserted membrane proteins of the nuclear envelope

核膜（NE）构成细胞核和细胞质之间的界面。尽管它在核结构中起作用，越来越多的证据表明NE也参与细胞过程的调节。编码NE蛋白的基因突变可引起多种影响横纹肌的疾病。这些普遍表达的基因突变如何导致疾病的组织特异性表现尚不清楚。使用综合蛋白质组学方法，Gerace实验室最近鉴定了67个以前未表征的NE的完整蛋白质。该项目将重点研究这些基因子集的产物的特征，这些基因位于与引起几种类型肌肉营养不良症（MDs）的突变相关的染色体区域。我们的目标是功能表征的一些候选基因，就其在细胞组织，功能和肌肉细胞分化中的作用。为此，将在培养的成肌细胞系统中单独抑制候选基因的表达，以筛选基因下调对细胞生长、细胞核和细胞质组织以及肌肉细胞分化的影响。本研究将有助于了解NE在细胞中整体蛋白的功能。使用肌肉细胞模型可以进一步研究候选基因在肌肉细胞分化中的功能。这将为NE蛋白引起MDs和其他疾病的机制提供见解。

The nuclear envelope (NE) constitutes the interface between the nucleus and the cytoplasm. Notwithstanding its role in nuclear structure, increasing evidence indicates that the NE also is involved in regulation of cellular processes. Mutations in genes coding for proteins of the NE can cause a variety of diseases affecting striated muscle. How mutations in these genes, which are ubiquitously expressed lead to a tissue-specific manifestation of disease is not clear. Using comprehensive proteomic methods the Gerace laboratory has recently identified 67 previously uncharacterized integral proteins of the NE. This project will focus on the characterization of the products of a subset of these genes that are located in chromosomal regions linked to mutations causing several types of muscular dystrophies (MDs). We aim to functionally characterize some of these candidate genes with respect to their role in cell organization, function and muscle cell differentiation. To this end, expression of the candidate genes will be individually repressed in a cultured myoblast cell system, to screen for the effects of gene down-regulation on cell growth, nuclear and cytoplasmic organization and on muscle cell differentiation. This study will contribute to the understanding of the function of integral proteins of the NE in cells. The use of a muscle cell model allows further to investigate the function of candidate genes in muscle cell differentiation. This will provide insights into the mechanism by which NE proteins cause MDs and other diseases.