Coilin, Cajal Bodies and Spinal Muscular Atrophy

线圈、卡哈尔体和脊髓性肌萎缩症

• 批准号: 6917639
• 负责人: A. Gregory Matera
• 金额: $ 35.38万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917639
• 关键词: HeLa cells; SDS polyacrylamide gel electrophoresis; disease /disorder etiology; disease /disorder model; gene expression; gene mutation; genetic models; genetically modified animals; intracellular transport; laboratory mouse; model design /development; molecular genetics; motor neurons; neuropathology; organelles; posttranscriptional RNA processing; progressive spinal muscular atrophy; protein biosynthesis; protein localization; protein protein interaction; protein structure function; protein transport; small nuclear ribonucleoproteins; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SMA) is a recessive neurogenetic disorder, caused by mutation of the human survival of motor neurons 1 (SMN1) gene. Patients with SMA typically die early in childhood. SMN protein is part of a large, oligomeric complex that plays an essential role in small nuclear ribonucleoprotein (snRNP) assembly. These small RNPs are required for pre-messenger RNA splicing, a process central to all eukaryotic cells. Small RNP biogenesis is compromised in patient cells, although the underlying cause of the SMA phenotype is not yet known. Thus learning more about SMN's role in the metabolism of snRNPs is essential not only to the study of RNA processing, but is important for our understanding of this devastating neuromuscular disease. Small RNP biogenesis is a stepwise process, taking place in multiple subcellular compartments. In mammalian cells, the SMN complex localizes to the nucleus and the cytoplasm. Whereas SMN is diffusely distributed throughout the cytosol, the nuclear fraction of the protein accumulates in Cajal bodies, colocalizing with an SMN-interacting protein called coilin. Cajal bodies are nuclear suborganelles involved in the maturation of snRNPs. The long-term goal of this proposal is to understand the molecular mechanisms that govern the biogenesis and subcellular localization of snRNPs. In other words, we seek to know how snRNPs are packaged, transported and delivered to their sites of action in the nucleus. In order to gain further insight into the biogenesis of snRNPs and its role in the pathogenesis of SMA, we have developed transgenic mouse and cell culture model systems to study SMN and Cajal bodies. Specific Aims of this proposal are: (1) to determine the function of the SMN complex in the import of small nuclear RNPs, (2) to identify factors required for SMN and snRNP assembly and import, and (3) to characterize the role of the SMN-coilin interaction at the organismal level.

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种隐性神经遗传疾病，由人类运动神经元存活1 （SMN1）基因突变引起。SMA患者通常在童年早期死亡。SMN蛋白是一个大的寡聚复合物的一部分，在小核核糖核蛋白（snRNP）组装中起重要作用。这些小RNA是前信使RNA剪接所必需的，这是所有真核细胞的核心过程。小RNP生物发生在患者细胞中受损，尽管SMA表型的根本原因尚不清楚。因此，更多地了解SMN在snRNPs代谢中的作用不仅对RNA加工的研究至关重要，而且对我们理解这种毁灭性的神经肌肉疾病也很重要。小RNP生物发生是一个循序渐进的过程，发生在多个亚细胞区室中。在哺乳动物细胞中，SMN复合物定位于细胞核和细胞质。虽然SMN在细胞质中弥散分布，但该蛋白的核部分在Cajal小体中积累，与一种称为卷蛋白的SMN相互作用蛋白共定位。Cajal小体是参与snRNPs成熟的核亚细胞器。该建议的长期目标是了解控制snRNPs的生物发生和亚细胞定位的分子机制。换句话说，我们试图知道snRNPs是如何被包装、运输和传递到它们在细胞核中的作用位点的。为了进一步了解snRNPs的生物发生机制及其在SMA发病机制中的作用，我们开发了转基因小鼠和细胞培养模型系统来研究SMN和Cajal小体。本提案的具体目标是：(1)确定SMN复合物在小核rnp进口中的功能，(2)确定SMN和snRNP组装和进口所需的因子，以及(3)表征SMN-coilin相互作用在组织水平上的作用。