Structure and Function of C. Difficile Toxins
艰难梭菌毒素的结构和功能
基本信息
- 批准号:9913462
- 负责人:
- 金额:$ 80.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-15 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAffinityBasic ScienceBindingBiologyBontoxilysinCRISPR/Cas technologyCell modelCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeClostridium difficileClostridium difficile tcdA proteinColitisCollaborationsComplementComplexCrystallizationCustomDataDeveloped CountriesDevelopmentDiarrheaDiseaseDockingEpithelialEpitheliumExhibitsExotoxinsFZD1 geneFZD2 geneFatty AcidsGastroenteritisGoalsHeparitin SulfateHumanInfectionInvestigationKnowledgeLengthLipoprotein (a)Low Density Lipoprotein ReceptorMass Spectrum AnalysisMediatingModelingMolecularMusMutagenesisNonesterified Fatty AcidsOrganoidsPathogenesisPathogenicityPathway interactionsProteinsPublishingReceptor CellResearchRoleSeriesSiteStructural ModelsStructureTherapeutic InterventionToxic effectToxinTropismWNT Signaling PathwayWorkalpha Toxinantibiotic-associated diarrheacrosslinkdesignexperimental studygenome wide screeninsightinterdisciplinary approachmembermolecular targeted therapiesmultidisciplinarymutantnovelnovel therapeutic interventionreceptorreceptor bindingresearch studysmall moleculetargeted treatmenttherapeutic developmenttooltranslational study
项目摘要
Project Summary
Clostridium difficile infection (CDI) is the most common cause of antibiotic-associated diarrhea
and gastroenteritis-associated death among developed countries, and it is classified as one of
the top three “urgent threats” by the US Centers for Disease Control and Prevention (CDC). The
disease associated with CDI is mainly mediated by two homologous exotoxins, TcdA and TcdB.
They target and disrupt the colonic epithelium, leading to diarrhea and colitis. Receptor-binding
is a critical step in the toxin’s action and largely determine toxin tropisms, and these receptors
are also molecular targets for therapeutic interventions. The goal of our proposal is to identify
and characterize toxin receptors, establish a structural basis for toxin-receptor recognition, and
harness this knowledge to gain a mechanistic understanding of the biology, pathogenesis, and
therapy of TcdA and TcdB. We will take a multi-disciplinary approach, bringing together the
expertise in toxin structure/function of Dr. Rongsheng Jin’s group with the expertise in toxin
receptor identification/pathogenesis of Dr. Min Dong’s group. This proposed work is built on
both our published work on identifying Frizzled (FZD) proteins as TcdB receptors, and extensive
preliminary data on toxin-receptor interactions. We will focus on three aims: (1) elucidate the
structural basis and pathogenic relevance of TcdB-FZD recognition;; (2) understand the structure
of TcdB and the influence of FZD binding;; and (3) identify and characterize novel TcdA
receptors through a CRISPR/Cas9 mediated genome-wide screens. These proposed studies
will provide a comprehensive understanding of toxin-receptor interactions and how they
contribute to the toxin biology and pathogenesis of TcdA and TcdB.
项目摘要
艰难梭菌感染(CDI)是抗生素相关性腹泻的最常见原因
和肠胃炎-在发达国家中与肠胃炎有关的死亡,它被列为
美国疾病控制和预防中心(CDC)的三大“紧急威胁”。
与CDI相关的疾病主要由两种同源外毒素TcdA和TcdB介导。
它们靶向并破坏结肠上皮,导致腹泻和结肠炎。
是毒素作用的关键步骤,并在很大程度上决定毒素的向性,
也是治疗干预的分子靶点。我们建议的目标是确定
并表征毒素受体,建立毒素受体识别的结构基础,
利用这些知识来获得对生物学,发病机制和
TcdA和TcdB的治疗。我们将采取多学科的方法,汇集
金荣盛博士团队的毒素结构/功能专业知识,具有毒素专业知识
闵东博士小组的受体鉴定/发病机制。这项拟议的工作是建立在
我们发表的关于鉴定卷曲蛋白(FZD)作为TcdB受体的工作,以及广泛的
毒素-受体相互作用的初步数据。我们将集中在三个目标:(1)阐明
TcdB-β FZD识别的结构基础和致病相关性;(2)了解TcdB-β FZD的结构
的TcdB和FZD结合的影响;(3)识别和表征新的TcdA
通过CRISPR/Cas9介导的全基因组筛选来检测受体。
将提供一个全面的了解毒素-受体的相互作用,以及如何,
有助于TcdA和TcdB的毒素生物学和发病机制。
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)
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Min Dong的其他文献
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{{ truncateString('Min Dong', 18)}}的其他基金
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Genome-wide CRISPR-Cas9 screens in insect cells to characterize insecticidal toxins
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- 批准号:
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- 批准号:
10551233 - 财政年份:2022
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- 资助金额:
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- 批准号:
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