How Regulated Proteolysis Controls Bacterial Virulence
How Regulated Proteolysis Controls Bacterial Virulence
批准号:
10443291
负责人:
Eduardo Groisman
金额:
$54.33万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1992
资助国家:
美国
项目状态:
未结题
起止时间:
1992-02-01 至 2027-02-28
关键词:
ATP-Dependent ProteasesAchievementAdaptor Signaling ProteinAmino Acid SequenceAntibiotic ResistanceBacteriaBacteria sigma factor KatF proteinBacterial PhysiologyBehaviorBiologicalCellsChimera organismDiseaseEnteralEnterobacteriaceaeEquilibriumEscherichia coliGastroenteritisGenesGrantGrowthHumanInfectionKineticsKnowledgeMediatingMessenger RNAMicrobeMolecular ChaperonesMusNatural HistoryPathogenesisPeptide HydrolasesPhysiologicalPlayPolymyxin BProteinsProteolysisRNAResearchResistanceRoleSalmonella typhimuriumSigma FactorSignal TransductionSpecificityStarvationStressTestingTissuesTyphoid FeverVirulenceVirulence FactorsYersinia pestisantagonistantibiotic tolerancedesignendopeptidase Laexperienceexperimental studyinnovationmacrophagenatural resistance-associated macrophage protein 1new therapeutic targetnovelnovel therapeutic interventionpathogenpreventprogramsprotein degradation
中文摘要
项目摘要
所有的病原体都需要蛋白质来致病。蛋白质丰度反映了一种微妙的平衡
合成和降解之间的相互作用对于致病和抗生素耐受性至关重要。蛋白
必须严格控制退化,因为其影响是不可逆转的。我们的目标是确定
相关的细菌物种,包括引起人类胃肠炎和鼠伤寒的
沙门氏菌肠道血清型鼠伤寒,部署蛋白水解作为一个重要的毒力策略。
我们将研究主毒力调节因子PhoP如何控制细菌的丰度、活性或
所有五种ATP依赖性蛋白酶:Lon、HslUV、ClpAP、ClpXP和FtsH的特异性。我们将
检查PhoP拮抗剂EIIANtr如何以phoP和离子依赖性方式蛋白水解
并确定PhoP和EIIANtr的蛋白水解在表达动力学中的作用,
当细菌在巨噬细胞内时,我们将揭示蛋白质和行为
由知之甚少的促毒蛋白酶HslUV控制;严格测试
基因沉默子H-NS的蛋白水解作用在外源基因表达中的作用,解决了基因沉默子H-NS在外源基因表达中的作用,
蛋白酶衔接子在感染期间防止蛋白质降解的机制。我们将
鉴定通过其5'前导序列控制毒力蛋白CspI和CspNP表达的信号
mRNA和定义介导非常低的生长的毒力蛋白MgtB的结构域。
Mg 2+和Slc 11 a1 +/+巨噬细胞中的存活。拟议的研究计划需要一个
全面的方法,包括技术和概念创新,以揭示重大的,
广泛适用的细菌生理学和致病机理原理以及新的治疗方法
克服抗生素耐药性的干预措施。
英文摘要
PROJECT SUMMARY
All pathogens require proteins to cause disease. Protein abundance reflects a delicate balance
between synthesis and degradation critical for pathogenesis and antibiotic tolerance. Protein
degradation must be tightly controlled because its effects are irreversible. We aim to determine
how related bacterial species, including the human gastroenteritis- and murine typhoid-causing
Salmonella enterica serovar Typhimurium, deploy proteolysis as an essential virulence strategy.
We will investigate how the master virulence regulator PhoP controls the abundance, activity, or
specificity of all five ATP-dependent proteases: Lon, HslUV, ClpAP, ClpXP, and FtsH. We will
examine how the PhoP antagonist EIIANtr is proteolyzed in a phoP- and lon-dependent manner
and identify the role that proteolysis of PhoP and EIIANtr plays in the expression kinetics of
virulence genes when bacteria are inside macrophages. We will uncover proteins and behaviors
controlled by the poorly understood virulence-promoting protease HslUV; critically test the role
that proteolysis of gene silencer H-NS plays in expression of foreign genes; and solve the
mechanism(s) by which protease adaptors prevent protein degradation during infection. We will
identify the signals governing expression of virulence proteins CspI and IraP via their 5' leader
mRNAs and define the domain(s) of the virulence protein MgtB mediating growth in very low
Mg2+ and survival in Slc11a1+/+ macrophages. The proposed research program takes a
comprehensive approach, including technical and conceptual innovations, to reveal significant,
broadly applicable principles in bacterial physiology and pathogenesis and new therapeutic
interventions that overcome antibiotic resistance.
期刊论文(0)
专著(0)
科研奖励(0)
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海外基金