Structure-Function Mapping of the Nuclear Pore Complex
Structure-Function Mapping of the Nuclear Pore Complex
批准号:
10394295
负责人:
JOHN D. AITCHISON
金额:
$66.62万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-03-01 至 2023-04-30
关键词:
BehaviorBindingCell NucleusCell physiologyChromatinCommunitiesComplexCytoplasmDNADefectDevelopmentDiseaseDissectionDrug DesignDrug TargetingElementsEpigenetic ProcessEukaryotic CellFoundationsFunctional disorderFutureGene ExpressionGene Expression ProfileGenesGenetic TranscriptionHumanKnowledgeLeadLightLinkMapsMediatingMessenger RNAMethodsMolecularMutationNatureNuclearNuclear EnvelopeNuclear Pore ComplexNuclear Pore Complex ProteinsNuclear StructureOncogenicOrthologous GenePathway interactionsPhenotypeProcessProtein ImportProteinsRegulationRegulator GenesResolutionRoleSignal TransductionSiteStructureTestingTherapeuticViralWorkYeastsdesignempoweredgenetic informationinsightmRNA Exportnucleocytoplasmic transportoutcome predictionpleiotropismvirtual
中文摘要
项目概要(摘要)
核孔复合体(NPC)是嵌入核膜中的大型圆柱形组件,位于核孔的中心,
核功能在两个相关的水平。首先,作为交通的监管机构,NPC控制着通往
DNA和从DNA传递遗传信息。其次,NPC是基因的重要调节因子,
结合染色质及其调节因子来控制表达状态,这是一种在生物学领域知之甚少的现象。
分子水平。在所有真核细胞中,这些关键作用涉及数十种相互作用的途径,
细胞功能的所有方面。因此,NPC的破坏导致许多人类疾病。
尽管如此,尽管核运输机制是一个有效和强大的药物靶点,NPC和
核转运机制还不是治疗策略的重要部分。可以说,有两个
出现这种情况的根本原因:(i)我们对NPC的结构了解不够,无法预测
它的行为;(ii)核运输机制影响了一系列令人困惑的细胞功能-因此,即使
尽管我们对它的结构有了深入的了解,但我们仍然需要互补的功能信息才能预测
有针对性地破坏运输途径的关键要素的结果。我们提出两个具体目标
它们以协同的方式相互通知。首先,我们将对疾病相关的
Nup复合物,重点是细胞质输出平台和内环的组成部分,
与致癌和发育缺陷有关。我们将使用我们已经使用的方法的增强版本,
成功部署,以生成这两个区域及其附着位点的高分辨率图。对
完成这项研究后,我们将以高精度绘制大部分NPC,使这两个地区能够
从整个全国人大会议的角度来看,其次,与此同时,我们将绘制疾病的功能图-
Nup复合体。我们将剖析与目标Nup复合物相关的功能,
确定与它们的改变相关的缺陷-测试这些Nups与
疾病,因为它们的破坏改变了关键的基因表达模式,其方式不同于其他疾病。
核孔蛋白。实现这些目标将产生前所未有的详细的NPC结构-功能图,
对于理解NPC的不同部分如何共同作用以确定其功能至关重要。这
该项目将揭示与人类NPC功能障碍相关的许多疾病的性质;旨在
最终打开核运输机制,以合理和预测药物设计。
英文摘要
PROJECT SUMMARY (Abstract)
The Nuclear Pore Complex (NPC) is a large cylindrical assembly embedded in the nuclear envelope, central for
nuclear function at two related levels. First, as a regulator of transport, the NPC controls signalling access to the
DNA and the passage of genetic information from DNA. Second, the NPC is an important regulator of genes by
binding chromatin and its regulators to control expression states, a phenomenon that is poorly understood at the
molecular level. These pivotal roles in all eukaryotic cells involve dozens of interacting pathways influencing
virtually all aspects of cellular function. As a consequence, disruption of the NPC leads to many human disorders.
Despite this, and though the nuclear transport machinery is a valid and powerful drug target, the NPC and the
nuclear transport machinery have not been a significant part of therapeutic strategies. Arguably, there are two
fundamental reasons why this is the case: (i) we do not know enough about the structure of the NPC to predict
its behavior; (ii) the nuclear transport machinery impacts a bewildering array of cellular functions - thus even with
a deep understanding of its structure, we still require complementary functional information to be able to predict
the outcome of the targeted disruption of key elements of the transport pathway. We propose two Specific Aims
that inform each other in a synergistic fashion. First, we will perform structural mapping of disease-associated
Nup complexes, focusing on components of the cytoplasmic export platform and inner rings that have been
linked to oncogenic and developmental defects. We will use enhanced versions of the methods we have already
successfully deployed to generate high resolution maps of these two regions and their attachment sites. On
completion of this study, we will have mapped most of the NPC at high precision, allowing the two regions to be
seen in the context of the whole NPC assembly. Second, and in parallel, we will map the functions of disease-
associated Nup complexes. We will dissect the functionalities associated with the target Nup complexes, and
determine the defects associated with their alteration - testing the hypothesis that these Nups are linked to
diseases because their disruption alters critical gene expression patterns in a manner distinct from other
nucleoporins. Realizing these aims will generate NPC structure-function maps in unprecedented detail and which
are essential to understanding how different parts of the NPC act together to determine its functionality. This
project will shed light on the nature of numerous disorders associated with human NPC dysfunction; aimed
ultimately to open the nuclear transport machinery to rational and predictive drug design.
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