Dynamic architecture of microtubule networks
微管网络的动态架构
基本信息
- 批准号:9900023
- 负责人:
- 金额:$ 39.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAffinityAllosteric RegulationArchitectureBeta CellBindingBinding ProteinsBiochemistryBiologicalBiophysicsBiopolymersCalcium SignalingCell CycleCell Cycle StageCell Differentiation processCell physiologyCellsComplexCuesCytoplasmGeometryGoalsGolgi ApparatusGrowthIndividualInterphaseIntracellular SpaceIntracellular TransportLaboratory ResearchLaboratory StudyMalignant NeoplasmsMetabolicMethodsMicrotubule-Organizing CenterMicrotubulesMolecularMolecular MotorsNational Institute of General Medical SciencesNerve DegenerationPatternPhysiologicalPhysiologyPlus End of the MicrotubulePositioning AttributePost-Translational Protein ProcessingProteinsPublishingRegulationResearchResearch SupportRoleSRC geneSignal TransductionSiteSlideSystemTubulinTumor Suppressor Proteinscell motilitycell typehuman diseaseinsightinsulin secretionnetwork architectureparalogous genepolymerizationprogramstrafficking
项目摘要
Abstract
Microtubules (MTs) are dynamic biopolymers, which serve as major trafficking highways in cells. MT-dependent
transport is critical for physiology of all cell types, and disturbance of MT networks underlies many human
diseases, from neurodegeneration to cancer. My laboratory studies global mechanisms whereby MT networks
are built to perfectly attribute to specific cellular functions. To a large extent, MT network organization is defined
by the sites from where new MTs initiate growth: the MT-organizing centers (MTOCs). MT architecture is also
influenced by local stabilization/disassembly and sliding of existing MTs. Furthermore, affinity of individual MTs
to molecular motors can be selectively modulated to provide fine-tuning of intracellular transport. While many
mechanisms tailor MT organization to specific cell functions, the MT network can also respond dynamically
according to signaling inputs and the physiological context. Molecular and spatial regulation of the MT network
and functional specialization of MTs therein are not well understood. My research program’s long-term goals
will be hugely facilitated by the MIRA, and include defining: how interphase MT networks are built and
regulated; specific mechanisms tailoring MT geometry to specific cellular needs; molecular and cell
biological mechanisms modulating MT network rebuilding during differentiation and different
physiological inputs; how MT networks with different geometries act in concert, yet switch functional
loads under changing signaling conditions; and, the methods whereby MTs collaborate with other
cellular systems to build intracellular space. Toward these global and interactive goals, we have published
numerous central discoveries in MT architecture organization (characterizing Golgi-derived MT networks
(GDMTs); the allosteric regulation of MT plus-end binding complex by CLASP proteins; and, metabolic regulation
of MT network for proper insulin secretion from beta cells), and MT function in cytoplasmic architecture (Golgi
assembly and integrity; c-Src transport; and dynamics of invasive actin protrusions, the podosomes). In the next
five years, I will extend the mechanistic and functional insight in three broad directions of my program’s extant
NIGMS-supported research. (I) Regarding the Golgi complex as an alternative MTOC, we will determine what
mechanisms underlie the spatial pattern of GDMT nucleation, how polarized GDMT arrays are organized, and
how MTOC functions of the Golgi are tuned by calcium signaling and differentiation cues. (II) Regarding the roles
of MT-binding proteins in MT network architecture, we will determine how paralogs of MT regulator CLASP exert
specific functions and uncover MT-dependent functions of the tumor suppressor RASSF1A. (III) Exploring how
the MT network provides architecture and functional organization within the cytoplasm, we will dissect the
interplay of post-translational modifications of tubulin and molecular motors that position the Golgi while
transitioning between cell-cycle stages in motile cells.
摘要
项目成果
期刊论文数量(0)
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Irina Kaverina其他文献
Irina Kaverina的其他文献
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{{ truncateString('Irina Kaverina', 18)}}的其他基金
Dynamic architecture and function of microtubule networks
微管网络的动态结构和功能
- 批准号:
10623051 - 财政年份:2018
- 资助金额:
$ 39.25万 - 项目类别:
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