Evaluate three v-SNAREs in regulated and constitutive TNF release from mast cells
评估肥大细胞调节和组成型 TNF 释放中的三种 v-SNARE
基本信息
- 批准号:10557868
- 负责人:
- 金额:$ 7.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAllergensAllergic inflammationAnimalsAsthmaBindingBiological AssayBone MarrowBreedingCell LineCell membraneCell surfaceCellsComplexConfocal MicroscopyCuesCytoplasmic GranulesDevelopmentDiseaseDouble-Stranded RNAEndosomesEndotoxinsEnzyme-Linked Immunosorbent AssayExocytosisFluorescenceGolgi ApparatusHarvestHeterozygoteIgEImmuneImmune responseInflammatoryInnate Immune ResponseInvestigationKnock-outKnockout MiceLengthMeasuresMediatingMembraneMembrane FusionMethodsMolecularMultivesicular BodyMusNatural ImmunityNaturePathway interactionsPatternPeritonealPlayPoly I-CProteolysisRecyclingRegulationRheumatoid ArthritisRoleSNAP receptorSNAP23 geneSignal TransductionStimulusTNF geneTestingThe Jackson LaboratoryTimeTumor PromotionVesicleViralWorkadaptive immunitycellubrevincombatexosomegranule cellinsightlate endosomemast cellnovel therapeutic interventionpathogenrelease factorresponsesyntaxinsyntaxin Atarget SNARE proteinstranscription factor
项目摘要
PROJECT SUMMARY
Mast cell-derived TNF (tumor necrosis factor) plays important roles in immune responses, but when in
excess, causes inflammatory disorders including asthma and rheumatoid arthritis. Unlike other TNF
producing cells, mast cells pre-store TNF in cytoplasmic granules, which can undergo rapid
exocytosis/degranulation under specific conditions. Mast cells can also be activated to promote TNF
transcription, and newly synthesized TNF is released over time via constitutive secretory carriers such as
Golgi-derived vesicles. Both regulated and constitutive TNF secretion require specific interactions
between vesicle/granule-anchored SNAREs (v-SNAREs) and SNAREs anchored to the plasma
membrane (the target membrane; hence t-SNAREs), resulting in the formation of trans-SNARE
complexes and concomitant membrane fusion. Exocytic trans-SNARE complexes in immune cells are
typically composed of a VAMP (v-SNARE), a SNAP23 (t-SNARE) and a syntaxin (t-SNARE). However,
the identities of the SNAREs that underscore TNF release from activated mast cells are largely unknown,
which has hindered the understanding of the stimulus-specific regulation of TNF exocytosis in these cells.
The overall objective of this proposal is to uncover the missing v-SNAREs required in regulated and
constitutive TNF secretion from primary mast cells. New evidence from our lab has suggested that TNF is
associated with exosomes within MVBs (multivesicular bodies; a type of late endosomes), which rely on
VAMP7 or Ykt6 (a unique, multi-purpose v-SNARE) to fuse with the plasma membrane. Meanwhile,
VAMP2 has recently emerged as the v-SNARE that mediates the exocytosis of Golgi-derived vesicles.
Based on these fresh insights, we hypothesize that mast cells employ VAMP7/Ykt6 and VAMP2 to
release prestored and newly synthesized TNF respectively in response to different environmental cues.
To test this hypothesis, we will exploit primary mast cells derived from KO mice and their wildtype
littermates to pursue two specific aims. Aim1 will assess the requirement of VAMP7 and Ykt6 in
acute/regulated TNF exocytosis. Aim2 will assess the requirement of VAMP2 in constitutive TNF
exocytosis. The completion of this study will delineate the catalytic machineries that drive TNF
exocytosis under different environmental conditions, setting a stage for revealing stimulus-specific
regulation of TNF release unique to mast cells.
项目总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Generating a New sgRNA Vector, pGL3-U6-sgRNA-PGK-mRFP-T2A-PuroR, to Improve Base Editing.
生成新的 sgRNA 载体 pGL3-U6-sgRNA-PGK-mRFP-T2A-PuroR,以改进碱基编辑。
- DOI:10.32371/jger/246146
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Ayo,TolulopeE;Xu,Hao
- 通讯作者:Xu,Hao
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{{ truncateString('Hao Xu', 18)}}的其他基金
Evaluate three v-SNAREs in regulated and constitutive TNF release from mast cells
评估肥大细胞调节和组成型 TNF 释放中的三种 v-SNARE
- 批准号:
10432701 - 财政年份:2022
- 资助金额:
$ 7.4万 - 项目类别:
Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences
选择性氮原子转移在生物医学科学中的应用
- 批准号:
10200095 - 财政年份:2020
- 资助金额:
$ 7.4万 - 项目类别:
Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences
选择性氮原子转移在生物医学科学中的应用
- 批准号:
10437832 - 财政年份:2020
- 资助金额:
$ 7.4万 - 项目类别:
Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences
选择性氮原子转移在生物医学科学中的应用
- 批准号:
9228383 - 财政年份:2014
- 资助金额:
$ 7.4万 - 项目类别:
Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences
选择性氮原子转移在生物医学科学中的应用
- 批准号:
9277033 - 财政年份:2014
- 资助金额:
$ 7.4万 - 项目类别:
Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences
选择性氮原子转移在生物医学科学中的应用
- 批准号:
9018047 - 财政年份:2014
- 资助金额:
$ 7.4万 - 项目类别:
Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences
选择性氮原子转移在生物医学科学中的应用
- 批准号:
8673127 - 财政年份:2014
- 资助金额:
$ 7.4万 - 项目类别:
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