Regulatory Mechanisms of GLUT4 Exocytosis
GLUT4胞吐作用的调控机制
基本信息
- 批准号:8437981
- 负责人:
- 金额:$ 33.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueBiological AssayBiological ModelsBlood GlucoseC2 DomainCell surfaceCellsChimeric ProteinsComplexDataDevelopmentDietDiseaseEpidemicExocytosisFatty acid glycerol estersFluorescence Resonance Energy TransferGLUT4 geneGlucoseGlucose TransporterGoalsInsulinInsulin ResistanceKineticsKnockout MiceKnowledgeLightLiposomesMeasuresMediatingMembraneMembrane FusionMolecularMunc18c proteinMusMuscleN-terminalNon-Insulin-Dependent Diabetes MellitusObesityPathogenesisPathway interactionsPhysiologicalPlayProcessProteinsReactionRecombinant ProteinsResearchRoleSNAP receptorSystemTherapeutic InterventionVesicleWorkbaseblood glucose regulationfeedingglucose uptakein vivoinsulin secretionloss of function mutationnovelnovel strategiespublic health relevancereconstitutionsyntaxin binding protein 1
项目摘要
DESCRIPTION (provided by applicant): As the epidemic of insulin resistance and type 2 diabetes emerges worldwide, there is an urgent need to understand how insulin maintains blood glucose homeostasis at the molecular level. A major function of insulin is to promote glucose uptake into muscle and adipose tissues, a process mediated by the glucose transporter GLUT4. Upon insulin stimulation, GLUT4 is relocated from intracellular storage vesicles to the cell surface through regulated exocytosis. The exocytosis of GLUT4 vesicles requires the SNARE proteins as the core fusion machinery, as well as a group of fusion regulators. Loss-of-function mutations of the SNAREs or fusion regulators abrogate insulin-triggered GLUT4 exocytosis and disrupt blood glucose homeostasis. Moreover, imbalances in the GLUT4 vesicle fusion proteins have been implicated in obesity-associated insulin resistance. While the physiological importance of the SNAREs and fusion regulators is clear, it remains poorly understood how they act in concert to mediate and regulate GLUT4 vesicle fusion. The overall goal of this proposal is to answer this key question using novel and complementary approaches. We will first define the molecular mechanisms and functional interactions of the vesicle fusion proteins using a novel reconstituted fusion system. We will use both recombinant proteins and native proteins isolated from mouse adipocytes. We will then characterize GLUT4 vesicle fusion proteins in 3T3-L1 adipocytes and in adipocytes isolated from knockout mice. Finally, we will determine whether and how the activities of the vesicle fusion proteins are impaired in insulin resistance, using hig fat diet-fed mice as a model system. If successfully accomplished, this research will substantially broaden our knowledge about the regulatory mechanisms of GLUT4 exocytosis. The findings will also shed light upon the diseases associated with glucose imbalances such as insulin resistance and type 2 diabetes, and will facilitate the development of novel strategies for
therapeutic intervention.
描述(由申请人提供):随着胰岛素抵抗和2型糖尿病在全球范围内的流行,迫切需要了解胰岛素如何在分子水平上维持血糖稳态。胰岛素的主要功能是促进葡萄糖摄取到肌肉和脂肪组织中,这是由葡萄糖转运蛋白GLUT 4介导的过程。在胰岛素刺激后,GLUT 4通过受调节的胞吐作用从细胞内储存囊泡重新定位到细胞表面。GLUT 4囊泡的胞吐作用需要SNARE蛋白作为核心融合机制,以及一组融合调节因子。SNARE或融合调节因子的功能丧失突变消除了胰岛素触发的GLUT 4胞吐作用,并破坏了血糖稳态。此外,GLUT 4囊泡融合蛋白的失衡与肥胖相关的胰岛素抵抗有关。虽然SNARE和融合调节因子的生理重要性是清楚的,但它们如何协同作用以介导和调节GLUT 4囊泡融合仍然知之甚少。本提案的总体目标是使用新颖和互补的方法回答这一关键问题。我们将首先定义的分子机制和功能相互作用的囊泡融合蛋白使用一种新的重组融合系统。我们将使用重组蛋白和从小鼠脂肪细胞分离的天然蛋白。然后,我们将在3 T3-L1脂肪细胞和从基因敲除小鼠分离的脂肪细胞中表征GLUT 4囊泡融合蛋白。最后,我们将以高脂饮食喂养的小鼠为模型系统,确定囊泡融合蛋白的活性是否以及如何在胰岛素抵抗中受损。如果成功完成,这项研究将大大拓宽我们对GLUT 4胞吐调控机制的认识。这些发现也将揭示与葡萄糖失衡相关的疾病,如胰岛素抵抗和2型糖尿病,并将促进开发新的策略,
治疗干预
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jingshi Shen其他文献
Jingshi Shen的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jingshi Shen', 18)}}的其他基金
Protein-membrane interactions in regulated exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
10380838 - 财政年份:2018
- 资助金额:
$ 33.17万 - 项目类别:
Protein-membrane interactions in regulated exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
9904731 - 财政年份:2018
- 资助金额:
$ 33.17万 - 项目类别:
Protein-Membrane Interactions in Regulated Exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
8641404 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Protein-Membrane Interactions in Regulated Exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
9005868 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Protein-Membrane Interactions in Regulated Exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
8792541 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Protein-Membrane Interactions in Regulated Exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
9212817 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Protein-Membrane Interactions in Regulated Exocytosis
调节胞吐作用中的蛋白质-膜相互作用
- 批准号:
8502214 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
相似国自然基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
- 批准号:81970721
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
- 批准号:
321208980 - 财政年份:2016
- 资助金额:
$ 33.17万 - 项目类别:
Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8827438 - 财政年份:2014
- 资助金额:
$ 33.17万 - 项目类别:
Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
- 批准号:
26450168 - 财政年份:2014
- 资助金额:
$ 33.17万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
- 批准号:
257256526 - 财政年份:2014
- 资助金额:
$ 33.17万 - 项目类别:
Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8828181 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8520690 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
- 批准号:
8629741 - 财政年份:2013
- 资助金额:
$ 33.17万 - 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
- 批准号:
23700778 - 财政年份:2011
- 资助金额:
$ 33.17万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
- 批准号:
21780261 - 财政年份:2009
- 资助金额:
$ 33.17万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
- 批准号:
7610781 - 财政年份:2007
- 资助金额:
$ 33.17万 - 项目类别: