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
微管(MT)是动态的生物聚合物,其充当细胞中的主要运输公路。MT依赖性
运输对于所有细胞类型的生理学是至关重要的,并且MT网络的干扰是许多人类疾病的基础。
从神经退化到癌症。我的实验室研究全球机制,
是为了完美地赋予特定的细胞功能而构建的。在很大程度上,MT网络组织是定义的
由新的MT开始增长的地点:MT组织中心(MTOC)。MT架构也是
受现有MT的局部稳定/拆卸和滑动的影响。此外,单个MT的亲和力
可以选择性地调节分子马达以提供细胞内转运的微调。虽然许多
机制使MT组织适合于特定的小区功能,MT网络也可以动态地响应
根据信号输入和生理背景。MT网络的分子和空间调控
和其中MT的功能专业化还没有很好地理解。我的研究项目的长期目标
将由MIRA提供巨大的便利,并包括定义:如何建立相间MT网络,
调节;特定机制定制MT几何结构以满足特定细胞需求;分子和细胞
分化和分化过程中MT网络重建的生物学机制
生理输入;具有不同几何结构的MT网络如何协同作用,但功能切换
在变化的信令条件下的负载;以及MT与其他MT协作的方法。
细胞系统来构建细胞内空间。为了实现这些全球性的互动目标,我们发布了
MT架构组织中的许多核心发现(表征高尔基衍生的MT网络
(GDMTs); CLASP蛋白对MT+末端结合复合物的变构调节;以及代谢调节
从β细胞适当分泌胰岛素的MT网络),以及MT在细胞质结构(高尔基体)中的功能
组装和完整性; c-Src转运;以及侵入性肌动蛋白突起(podosomes)的动力学)。未来
五年后,我将在我的计划的现存的三个广泛的方向扩展机械和功能的见解
NIGMS支持的研究。(I)关于高尔基复合体作为替代MTOC,我们将确定
GDMT成核的空间模式,极化GDMT阵列如何组织,
高尔基体的MTOC功能是如何通过钙信号和分化信号调节的。(II)角色方面的
MT结合蛋白的MT网络架构,我们将确定如何旁系同源的MT调节CLASP发挥
特异性功能,并揭示肿瘤抑制因子RASSF1A的MT依赖性功能。(III)探索如何
MT网络提供了细胞质内的结构和功能组织,我们将剖析
微管蛋白的翻译后修饰和定位高尔基体的分子马达的相互作用,
运动细胞中细胞周期阶段之间的转变。
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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