Connecting the Genome to the Cytoplasm

连接基因组与细胞质

• 批准号: 7228567
• 负责人: Pamela A Silver
• 金额: $ 46.79万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228567
• 关键词: Address; Affect; Amyotrophic Lateral Sclerosis; Cell Nucleus; Cells; Complex; Cytoplasm; Defect; Diffusion; Disease; Disseminated Malignant Neoplasm; Drug effect disorder; Gene Expression; Gene Expression Regulation; Gene Fusion; Genes; Genome; Grant; Growth; Hereditary Disease; Human Genome; Image; Kinetics; Lead; Localized; Location; Malignant Neoplasms; Mammalian Cell; Messenger RNA; Modeling; Molecular; Movement; Muscular Dystrophies; Mutation; Normal Cell; Nuclear; Nuclear Export; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Nucleoplasm; Nucleoporin Gene; Numbers; Pathway interactions; Play; Process; Production; Protein Export Pathway; Proteins; RNA-Binding Proteins; Reaction; Regulation; Role; Side; Specificity; Stimulus; Testing; Translations; Viral Proteins; Work; Yeasts; alpha-mating factor; cancer cell; case-based; cell growth; design; human disease; in vivo; insight; mRNA Export; new technology; nucleocytoplasmic transport; programs; research study; response

DESCRIPTION (provided by applicant): This proposal addresses issues relevant to normal cell growth and to disease: the spatial organization within the nucleus, and how the nucleus communicates with the cytoplasm and the cell exterior. The focus is on the relationship between the organization of the genome and the processing and export of mRNAs. The movement of mRNAs through the nucleoplasm and out of the nucleus to cytoplasmic locations is an elaborately orchestrated and regulated process. The pathway of mRNA export includes: proper processing, packaging into protein-RNA complexes, targeting and movement through the nuclear pore complex (NPC) and release into the cytoplasm for translation. In some cases, mRNAs are further localized within the cytoplasm. This proposal focuses on the spatial organization of the genome with respect to its interactions with the NPC, nuclear export factors, RNA binding proteins, and the processing and movement of mRNAs out of the nucleus. The Specific Aims are designed to determine: 1) the requirements for gene movement with respect to the nuclear export machinery; 2) the connection between intranuclear gene location, mRNA export and cytoplasmic mRNA location; 3) the interaction of the genome with the nuclear export machinery; and 4) the identification and specificity of recruitment of RNA binding proteins important for mRNA processing and export. The regulation of mRNA dynamics is key to certain genetic diseases, the function of some viral proteins, the response of cells to growth stimuli, and, in some cases, the basis for drug action. We have come to appreciate the complex interplay between gene expression, nuclear organization and transport. This inherent complexity can affect growth status and disease states. Moreover, defects in mRNA processing are associated with a number of diseases including metastatic cancers, muscular dystrophy and amyotrophic lateral sclerosis. The experiments proposed in this grant will not only lead to new basic insights but also to new ways to analyze on a genome-wide level the situation in genetically defective cells and certain cancers.

描述（由申请人提供）：该提案解决了与正常细胞生长和疾病相关的问题：核中的空间组织，以及核如何与细胞质和细胞外部通信。重点是基因组组织与mRNA的处理和出口之间的关系。 mRNA通过核质和从细胞核向细胞质位置的运动是一个精心策划的调节过程。 mRNA输出的途径包括：正确加工，将蛋白质-RNA复合物包装到核孔复合物（NPC）中，并释放到细胞质中进行翻译。在某些情况下，mRNA进一步定位在细胞质中。该建议集中于基因组与NPC的相互作用，核输出因子，RNA结合蛋白以及mRNA从细胞核中的加工和移动的空间组织。具体目的旨在确定：1）基因运动对核出口机械的要求； 2）核内基因位置，mRNA输出和细胞质mRNA位置之间的联系； 3）基因组与核出口机械的相互作用； 4）RNA结合蛋白募集的鉴定和特异性对于mRNA加工和出口很重要。 mRNA动力学的调节是某些遗传疾病的关键，某些病毒蛋白的功能，细胞对生长刺激的反应以及在某些情况下是药物作用的基础。我们已经欣赏基因表达，核组织和运输之间的复杂相互作用。这种固有的复杂性会影响生长状况和疾病状态。此外，mRNA处理的缺陷与多种疾病有关，包括转移性癌症，肌肉营养不良和肌萎缩性侧面硬化症。该赠款中提出的实验不仅会导致新的基本见解，还将为全基因组水平分析遗传缺陷细胞和某些癌症的情况分析新方法。