Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects
颗粒酶A介导的γ9δ2 T细胞结核病保护作用的机制研究
基本信息
- 批准号:10268163
- 负责人:
- 金额:$ 3.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-22 至 2024-07-21
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAdultAerosolsAntigensApoptosisApoptosis PromoterBCG VaccineBiological AssayBiological ModelsBiological ProcessCD8B1 geneCatalysisCause of DeathCell LineCell physiologyCellsCessation of lifeChemicalsCleaved cellCommunicable DiseasesControl GroupsCytoplasmic GranulesCytoprotectionDiseaseDoseEnvironmentEnzymesEpidemicExtracellular ProteinFrequenciesGene ExpressionGenesGenus MycobacteriumGoalsGranzymeGrowthImmune responseImmunocompromised HostImmunotherapeutic agentIn VitroIndividualInfection preventionInflammatoryInflammatory ResponseInterleukin-1 betaInvestigationKnock-outLeadLiteratureLungMediatingMonitorMulti-Drug ResistanceMycobacterium tuberculosisMycobacterium tuberculosis antigensNatural Killer CellsNaturePathologyPathway interactionsPatientsPharmaceutical PreparationsPhysiciansPhysiologicalPoint MutationPopulationPost-Translational Protein ProcessingProtein AnalysisProteinsProteomeProteomicsRecombinantsResearch ProposalsResistanceRoleRouteScientistSerine ProteaseSiteSpottingsSurfaceT-Cell ReceptorT-LymphocyteTNF geneTestingTrainingTryptaseTuberculosisVaccinatedVaccinationVariantbasebiological adaptation to stresscareercytokinecytotoxicdesigndifferential expressionendoplasmic reticulum stressexperimental studyextracellularhuman modelimmunocytochemistryinfection rateinhibitor/antagonistmacrophagemedication compliancemonocytemycobacterialnonhuman primatenovelnovel vaccinesoverexpressionpathogenperforinprotective effectprotein expressionreceptorskillstransmission processvaccine accessvaccine trialγδ T cells
项目摘要
ABSTRACT
This proposal will determine the mechanism responsible for Granzyme A (GzmA)-mediated inhibition of
Mycobacterium tuberculosis (Mtb) growth, to better understand the host immune response. One fourth of the
world’s population is infected with Mtb. Currently, BCG strains are the only vaccines available to protect
against tuberculosis (TB). γ9δ2 T cells are found at higher frequencies in lungs, which is the primary site of Mtb
infection. Our lab has previously shown that TB specific γ9δ2 T cells secrete GzmA upon stimulation with
mycobacterial antigens. Furthermore, our lab has demonstrated that GzmA, when released by TB-specific γδ T
cells, inhibits the intracellular replication of the pathogen. GzmA is a serine protease found within cytotoxic
granules of NK cells, CD8+ CTL, and γδ T cells. It has tryptase activity cleaving basic residues after Arg or Lys,
and was originally thought to be an inducer of apoptosis in the target cell in a perforin-dependent manner
similar to Granzyme B. However, more recent literature has shown that GzmA at a physiologic concentration
(nM) does not cause apoptosis. Instead, it induces monocytes/macrophages to produce pro-inflammatory
cytokines. Our lab has shown that GzmA in a perforin-independent manner induces the infected macrophage
to secrete pro-inflammatory cytokines, such as TNF-alpha and IL-1β, and inhibits the intracellular growth of
mycobacteria. A transcriptomal analysis was performed, which failed to identify the mechanism of GzmA-
mediated inhibition. We hypothesize that given the proteolytic nature of GzmA, a rational approach to
investigate this mechanism would be to perform a proteomic analysis. GzmA route of entry and enzyme
catalysis will be studied in Aim 1 to better understand the necessary steps for inhibition. In Aim 2, the
Endoplasmic Reticulum (ER) stress response and purinergic channel activation will be interrogated: these two
pathways were discovered during preliminary proteomic experiments, and will be modulated by knocking out
genes or inhibiting key factors in cell lines and/or primary cells. Finally, additional global proteomic screens will
be conducted to detect other differentially expressed proteins in Aim 3. Overall, this project will help in the
design of novel immunotherapeutic and/or chemotherapeutic solutions for TB protection and will aid the WHO’s
current goal to decrease TB deaths of 90% by 2030. A proposed comprehensive training plan includes these
exciting studies that will allow me to develop needed skills for my career goal to become a successful
independent physician-scientist.
抽象的
该提案将挖掘负责粒酶A(GZMA)介导的侵犯的机制
结核分枝杆菌(MTB)生长,以更好地了解宿主免疫反应。
世界人口被MTB感染。
针对结核病(TB)。
感染。
分枝杆菌抗原。
细胞,抑制病原体的细胞内反映。
NK细胞的颗粒,CD8+ CTL和γδT细胞具有胰蛋白酶活性在ARG或LYS之后裂解基本居民
最初是以深度蛋白的方式成为目标细胞中凋亡的诱导剂
类似于GranzymeB。然而,最近的文献表明,GZMA处于
(NM)不会引起凋亡。
细胞因子。
分泌促炎性细胞因子,例如TNF-ALPHA AL-1β,并抑制细胞内生长
分枝杆菌进行了转录组分析,未能确定GZMA-
介导的遗传性。
研究这种机制将进行蛋白质组学分析。
将在AIM 1中研究催化,以更好地了解AIM 2中的必要步骤。
内质网(ER)应力反应和嘌呤能通道激活将弯曲:这两个
在预后蛋白质组学实验中发现了途径,并将通过敲除
基因或抑制细胞lin和/或原代细胞中的关键因素。
进行AIM 3中检测到其他差异表达的蛋白质。总的来说,该项目将在
新颖的免疫治疗和/或化学治疗剂的设计用于结核病保护,将有助于谁
到2030年,目前将结核病死亡人数降低90%的目标。
激动人心的研究将使我能够为自己的职业目标发展所需的技能,以成为成功
独立的医师科学家。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Valerio Rasi其他文献
Valerio Rasi的其他文献
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{{ truncateString('Valerio Rasi', 18)}}的其他基金
Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects
颗粒酶A介导的γ9δ2 T细胞结核病保护作用的机制研究
- 批准号:
9911040 - 财政年份:2020
- 资助金额:
$ 3.15万 - 项目类别:
Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects
颗粒酶A介导的γ9δ2 T细胞结核病保护作用的机制研究
- 批准号:
10669084 - 财政年份:2020
- 资助金额:
$ 3.15万 - 项目类别:
Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects
颗粒酶A介导的γ9δ2 T细胞结核病保护作用的机制研究
- 批准号:
10445297 - 财政年份:2020
- 资助金额:
$ 3.15万 - 项目类别:
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