Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level
破译涉及分子水平上蛋白质-核酸相互作用的基本生物过程
基本信息
- 批准号:10622948
- 负责人:
- 金额:$ 26.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnti-Bacterial AgentsAntimicrobial ResistanceBacteriaBiochemistryBiologicalBiological ProcessCessation of lifeComplexCryoelectron MicroscopyCuesDNADNA Repair PathwayDevelopmentEnzymesGenetic TranscriptionGlutamate-Ammonia LigaseGoalsGram-Positive BacteriaHealthHumanInvestigationLife Cycle StagesLinkMetabolic PathwayMicrobeMitochondriaMolecularMulti-Drug ResistanceNitrogenNucleic AcidsNutrient availabilityPathogenesisPharmaceutical PreparationsProcessProteinsProtozoaRNA EditingSecond Messenger SystemsSignal PathwaySignal TransductionSourceStreptomycesStructureTherapeuticantimicrobial drugbacterial resistancecombatdrug resistant microorganismenvironmental changein vivointerestmicrobialmicrobial diseasenovelphosphoric diester hydrolaserational designtherapeutic target
项目摘要
ABSTRACT
The central goal of the Schumacher lab is to deduce molecular principles governing fundamental biological
processes involving protein-nucleic acid interactions. These investigations focus on processes in microbes and
intersect with the lab’s interests in microbial pathogenesis. Indeed, while the main goal is to elucidate biological
mechanisms at the atomic level, these studies also provide potential targets for the development of urgently
needed antimicrobial agents. Alarmingly, recent estimates suggest that deaths from antimicrobial resistance
bacteria may exceed 10 million deaths worldwide by 2050 if steps are not taken to generate new treatments.
The specific processes we investigate include transcription, DNA organization and RNA editing. Bacteria must
be able to sense and respond to environmental changes for their survival and in some cases, proper
development, so our studies on transcription focus on important networks and address how environmental
cues are signaled and detected by transcription switches. Streptomyces bacteria represent the main source of
antibacterial and other key drugs, which they generate concomitant with development. Thus, understanding
their developmental lifecycle has been of significant interest for decades, although it is a mystery what drives
this process. Our studies in the last few years have revealed that this developmental switch is controlled by the
second messenger, c-di-GMP, functioning through two global transcription regulators, BldD and WhiG. These
regulators control the first and second steps in Streptomyces development, respectively, but how c-di-GMP
levels are sensed and signaled to these regulators are unknown and is a question we will address in this
proposal. Initial studies unveiled a possible link between WhiG and a c-di-GMP phosphodiesterase, possibly
indicating colocalization as a mechanism to control the second developmental step, which we will investigate.
Studies will also be performed to analyze c-di-GMP levels and identify and characterize additional c-di-GMP
modulated developmental regulators. Using a combination of cryo-EM, biochemistry and in vivo studies, we will
also dissect the molecular mechanism by which nitrogen levels are sensed in Gram-positive bacteria by the
novel Glutamine Synthetase-GlnR signaling pathway whereby the central enzyme for a metabolic pathway
(GS) directly transduces nutrient availability to its master transcription regulator (GlnR). Finally, we will
elucidate the signal and mechanism behind the first SOS-independent DNA repair pathway in bacteria.
Another focus of the lab is the unusual RNA editing process in the mitochondria of kinetoplastid parasitic
protozoans called kinetoplastid RNA (kRNA) editing. A recently identified accessory complex, the MRB1
complex, is required for this process. However, the structure and mechanisms of action of this complex are
completely unknown. We will obtain structures of this complex and dissect its various molecular functions in
editing. These combined studies will elucidate fundamental biological processes at the molecular level, leading
to the discovery of potential chemotherapeutic targets against microbial diseases.
摘要
项目成果
期刊论文数量(0)
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Maria Schumacher其他文献
Maria Schumacher的其他文献
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{{ truncateString('Maria Schumacher', 18)}}的其他基金
Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level
破译涉及分子水平上蛋白质-核酸相互作用的基本生物过程
- 批准号:
10543420 - 财政年份:2019
- 资助金额:
$ 26.84万 - 项目类别:
Deciphering fundamental biological processes involving protein-nucleic acid interactions at the molecular level
破译涉及分子水平上蛋白质-核酸相互作用的基本生物过程
- 批准号:
10319963 - 财政年份:2019
- 资助金额:
$ 26.84万 - 项目类别:
Assembly and partition mechanism of Walker-box based segregation machinery
基于Walker-box的分离机械的组装和分离机构
- 批准号:
8941756 - 财政年份:2015
- 资助金额:
$ 26.84万 - 项目类别:
Complete atomic dissection of the B. subtilis nitrogen regulatory pathway
枯草芽孢杆菌氮调节途径的完整原子解剖
- 批准号:
9313913 - 财政年份:2015
- 资助金额:
$ 26.84万 - 项目类别:
Complete atomic dissection of the B. subtilis nitrogen regulatory pathway
枯草芽孢杆菌氮调节途径的完整原子解剖
- 批准号:
9118245 - 财政年份:2015
- 资助金额:
$ 26.84万 - 项目类别:
Protein Design, Expression and Purification Core
蛋白质设计、表达和纯化核心
- 批准号:
8931201 - 财政年份:2015
- 资助金额:
$ 26.84万 - 项目类别:
Assembly and partition mechanism of Walker-box based segregation machinery
基于Walker-box的分离机械的组装和分离机构
- 批准号:
9118256 - 财政年份:2015
- 资助金额:
$ 26.84万 - 项目类别:
Structural mechanism of DNA segregation by the pSK41 par system
pSK41 par系统DNA分离的结构机制
- 批准号:
8236042 - 财政年份:2009
- 资助金额:
$ 26.84万 - 项目类别:
Structural mechanism of DNA segregation by the pSK41 par system
pSK41 par系统DNA分离的结构机制
- 批准号:
7728001 - 财政年份:2009
- 资助金额:
$ 26.84万 - 项目类别:
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