Nuclear bodies and ribonucleoprotein biogenesis

核体和核糖核蛋白生物合成

• 批准号: 7759641
• 负责人: MICHAEL D HEBERT
• 金额: $ 27.84万
• 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/7759641
• 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）：核是高度组织的，并包含不同的领域，领土和身体。有趣的是，细胞核的组织在细胞类型和发育阶段之间有所不同。例如，胎儿神经元细胞核中包含Cajal体（CBS）和宝石。相反，成年神经元细胞不包含宝石，并且在该结构域中发现的蛋白质定位于CBS。 GEM含有运动神经元（SMN）蛋白的存活，该蛋白在大多数神经退行性疾病肌肉萎缩症患者中被突变。尚未描述GEM的功能，但是当前的证据暗示CB是核糖核蛋白（RNP）成熟的位点。由于RNP对于MRNA和RRNA前处理至关重要，因此活跃从事转录（例如神经元和癌细胞）的细胞包含明显的CBS。癌症可能诱导CB形成，但其他疾病可能会破坏CB功能。两种此类疾病是脊柱肌肉萎缩和Machado-Joseph疾病。我们假设不同细胞类型之间观察到的核体组织中观察到的发育多样性是RNP生物发生的最有效核构型的体现。我们怀疑Coilin的翻译后修饰状态，COILIN是CB标记蛋白，在哺乳动物细胞CB形成和组成中起重要作用，随着每种核构型的变化。我们进一步假设，破坏核的功能组织的疾病会不利地影响RNP的成熟，从而减少了MRNA剪接。在此应用中，我们提出了旨在建立核组织和RNP生物发生的核组织层次结构的实验。我们还将定义对CB形成至关重要的螺旋蛋白中的磷酸化沉积物，并测试Machado-Joseph病中RNP生物发生是否阻碍。这样一来，我们将在正常状态和疾病状态下大大扩展对核功能组织的了解。 公共卫生相关性：胎儿和成人组织之间细胞核的组织存在明显的差异。我们怀疑蛋白质卷蛋白在形成两个称为Cajal体和宝石的核结构中起着重要作用。某些疾病，例如癌症和某些神经退行性疾病，可能会改变Cajal的身体和GEM活性。