Nuclear bodies and ribonucleoprotein biogenesis

核体和核糖核蛋白生物合成

• 批准号: 7599672
• 负责人: MICHAEL D HEBERT
• 金额: $ 28.12万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599672
• 关键词: Adult; Affect; Biogenesis; Biological; Biological Assay; Body Composition; Cell Cycle; Cell Line; Cell Nucleus; Cell physiology; Cells; Development; Disease; Employee Strikes; Frequencies; Genetic Transcription; Interphase; Knowledge; Lead; Lung; MJD1 protein; Machado-Joseph Disease; Malignant Neoplasms; Mammalian Cell; Maps; Mitosis; Modification; Monitor; Mutate; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Inclusion; Nuclear Structure; Patients; Phosphorylation; Play; Post-Translational Protein Processing; Primer Extension; Proteins; RNA Interference; RNA Splicing; RNase protection assay; Reporter; Resources; Ribonucleoproteins; Role; SMN protein (spinal muscular atrophy); Site; Site-Directed Mutagenesis; Spinal Cord; Spinal Muscular Atrophy; Staging; Structure; Techniques; Testing; Tissues; Transcript; base; cancer cell; cell type; design; fetal; insight; mRNA Precursor; mutant; public health relevance; rRNA Precursor; research study; tandem mass spectrometry

DESCRIPTION (provided by applicant): The nucleus is highly organized and contains distinct domains, territories and bodies. Intriguingly, the organization of the nucleus varies between cell type and developmental stage. Fetal neuronal cell nuclei, for example, contain Cajal bodies (CBs) and Gems. On the contrary, adult neuronal cells do not contain Gems and the proteins found within this domain localize to CBs. Gems contain the Survival of Motor Neuron (SMN) protein, which is mutated in most patients with the neurodegenerative disorder Spinal Muscular Atrophy. No function for Gems has been described, but current evidence implicates the CB as the site for maturation of ribonucleoproteins (RNPs). Since RNPs are vital for pre- mRNA and pre-rRNA processing, cells actively engaged in transcription (e.g. neuronal and cancer cells) contain prominent CBs. Cancer may induce CB formation, but other diseases may disrupt CB function. Two such diseases are Spinal Muscular Atrophy and Machado-Joseph disease. We hypothesize that the observed developmental diversity in nuclear body organization between different cell types is a manifestation of the most efficient nuclear configuration for RNP biogenesis. We suspect that the post-translational modification status of coilin, the CB marker protein that plays an important role in mammalian cell CB formation and composition, varies with each nuclear configuration. We further hypothesize that diseases which disrupt the functional organization of the nucleus adversely affect RNP maturation, resulting in decreased pre-mRNA splicing. In this application, we propose experiments designed to establish a hierarchy of nuclear organization with respect to nuclear bodies and RNP biogenesis. We will also define the phospho-residues in coilin that are crucial for CB formation, and test if RNP biogenesis is impeded in Machado-Joseph disease. In so doing, we will significantly expand our knowledge of the functional organization of the nucleus in both normal and disease states. PUBLIC HEALTH RELEVANCE: There is a striking difference in the organization of the nucleus between fetal and adult tissues. We suspect that the protein coilin plays an important role in the formation of two nuclear structures known as Cajal bodies and Gems. Certain diseases, such as cancer and some neurodegenerative disorders, may alter Cajal body and Gem activity.

描述（由申请人提供）：核心组织严密，包含不同的领域、领土和机构。有趣的是，细胞核的组织因细胞类型和发育阶段而异。例如，胎儿神经元细胞核包含卡哈尔体 (CB) 和宝石。相反，成体神经元细胞不包含 Gems，并且在该结构域内发现的蛋白质定位于 CB。宝石含有运动神经元存活 (SMN) 蛋白，该蛋白在大多数患有神经退行性疾病脊髓性肌萎缩症的患者中发生突变。尚未描述 Gems 的功能，但目前的证据表明 CB 是核糖核蛋白 (RNP) 成熟的位点。由于 RNP 对于 mRNA 前体和 rRNA 前体加工至关重要，因此积极参与转录的细胞（例如神经元和癌细胞）含有显着的 CB。癌症可能会诱导 CB 形成，但其他疾病可能会破坏 CB 功能。两种这样的疾病是脊髓性肌萎缩症和马查多-约瑟夫病。我们假设观察到的不同细胞类型之间核体组织的发育多样性是 RNP 生物发生最有效的核构型的表现。我们怀疑，coilin（一种在哺乳动物细胞 CB 形成和组成中起重要作用的 CB 标记蛋白）的翻译后修饰状态随每种核构型的不同而变化。我们进一步假设破坏细胞核功能组织的疾病会对 RNP 成熟产生不利影响，导致前 mRNA 剪接减少。在此应用中，我们提出了旨在建立关于核体和 RNP 生物发生的核组织层次结构的实验。我们还将定义线圈蛋白中对 CB 形成至关重要的磷酸残基，并测试马查多-约瑟夫病中 RNP 生物发生是否受到阻碍。通过这样做，我们将显着扩展我们对正常和疾病状态下细胞核功能组织的了解。 公共卫生相关性：胎儿组织和成人组织之间的细胞核组织存在显着差异。我们怀疑蛋白质线圈蛋白在称为卡哈尔体和宝石的两种核结构的形成中发挥着重要作用。某些疾病，例如癌症和一些神经退行性疾病，可能会改变卡哈尔体和宝石活性。