PARP1 and PARylation as novel effectors of gut inflammation
PARP1 和 PARylation 作为肠道炎症的新型效应物
基本信息
- 批准号:10679646
- 负责人:
- 金额:$ 61.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ADP ribosylationAdenosine Diphosphate RiboseAffectAmino AcidsBiologyCaringCell CompartmentationCell physiologyCellular biologyChronicClinicalCoenzyme AColitisColonColonic inflammationComplexDNA Repair EnzymesDataDiseaseDisease ProgressionEnergy MetabolismEpithelial CellsEpitheliumEtiologyFDA approvedGenetic TranscriptionGerm-FreeGut MucosaHomeostasisHumanHyperactivityImmune responseImmune systemImpairmentIn VitroInflammationInflammation MediatorsInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInjuryKnock-outMaintenanceMarketingMediatingMetabolicMicrobeMindModelingMucositisMucous MembraneMusOnset of illnessOutcomePathogenesisPatientsPlayPoly(ADP-ribose) PolymerasesPolymerasePost-Translational Protein ProcessingPredispositionProteinsRecoveryRegulatory T-LymphocyteRelapseResearchRiskRoleSirtuinsStructureSupplementationSystemTestingTimeWorkanti agingbacterial communitycandidate identificationcofactorcommensal bacteriacommensal microbescomparativedesignefficacy evaluationfecal transplantationgastrointestinalgastrointestinal epitheliumgut inflammationgut microbiotahost microbiomeimprovedin vivoinhibitorlarge bowel Crohn&aposs diseasemicrobial communitymicrobial compositionmicrobiome alterationmicrobiotamurine colitisnicotinamide-beta-ribosidenovelnovel strategiesoral supplementationpharmacologicprotein functionpublic health relevancetargeted treatment
项目摘要
Despite recent advances in the understanding host-microbiome interactions in the pathogenesis of Inflammatory Bowel Diseases (IBD), the complexity of the host’s response to changing gut microbiota is daunting and still incompletely understood. In this proposal, we show that poly-ADP-ribosylation (PARylation), a post-translational modification that involves the enzymatic transfer of ADP-ribose (ADPr) from NAD+ to specific amino acids of target proteins, plays key roles as a mediator of inflammatory response in the gut. For the first time, we provide evidence that PARP1 is the primary PAR writer in the colon, where it serves as a powerful transcriptional modulator. Commensal bacteria are necessary for mucosal PARP1 activity and PARylation and, reciprocally, PARP1 controls the microbial composition and metabolic activity, modulates colonic epithelial barrier function, and restricts the mucosal Treg compartment. Importantly, human and murine colitis is associated with mucosal hyperPARylation, which can be transferred to germ-free mice with complex microbial community from IBD patients. Total or epithelial-specific knockout of PARP1 (or pharmacological inhibition) protect from and promote recovery from mucosal injury. Based on these novel preliminary observations, we hypothesized that hyperPARylation is a significant contributor to mucosal inflammation and impaired mucosal restitution via both extrinsic (interaction with gut microbiota) and intrinsic effects in the colonic mucosa. We will address this hypothesis in the following three well-integrated, but not mutually contingent specific aims, which will: (1) Define the role of NAD+ depletion vs. hyperPARylation as putative culprits in the pathogenesis of experimental colitis (2) Define the role of PARP1 and PARylation in colitis mediated by human IBD microbiota; and (3) Mechanistically define the roles of PARP1 in the highly interactive relationship between gut microbiota and epithelial barrier function and mucosal restitution.in the inflamed colon. This novel research plan will greatly advance the field of fundamental mucosal biology and will offer targeting of PARP1 activity as a potential IBD therapy.
尽管最近在理解炎症性肠病(IBD)发病机制中的宿主-微生物组相互作用方面取得了进展,但宿主对变化的肠道微生物群的反应的复杂性令人生畏,并且仍然没有完全理解。在这个提议中,我们表明,聚ADP核糖基化(PAR化),一种翻译后修饰,涉及ADP-核糖(ADPr)从NAD+到靶蛋白的特定氨基酸的酶促转移,在肠道炎症反应中起着关键作用。这是第一次,我们提供的证据表明,PARP 1是主要的PAR作家在结肠,在那里它作为一个强大的转录调节剂。共生细菌对于粘膜PARP 1活性和PAR化是必需的,并且,PARP 1控制微生物组成和代谢活性,调节结肠上皮屏障功能,并限制粘膜Treg区室。重要的是,人类和小鼠结肠炎与粘膜高PAR化相关,其可以从IBD患者转移到具有复杂微生物群落的无菌小鼠。PARP 1的完全或上皮特异性敲除(或药理学抑制)保护粘膜免受损伤并促进粘膜损伤的恢复。基于这些新的初步观察结果,我们假设高PAR化是通过结肠粘膜中的外在(与肠道微生物群的相互作用)和内在效应导致粘膜炎症和粘膜恢复受损的重要因素。我们将在以下三个充分整合但不相互关联的具体目标中阐述这一假设,这三个目标将:(1)定义NAD+消耗相对于PAR高化作为实验性结肠炎发病机制中的假定罪魁祸首的作用(2)定义PARP 1和PAR高化在由人IBD微生物群介导的结肠炎中的作用;和(3)机械地定义PARP 1在肠道微生物群和上皮屏障功能与粘膜之间的高度相互作用关系中的作用restitution.in,炎症结肠。这项新的研究计划将大大推进基础粘膜生物学领域,并将提供PARP 1活性靶向作为一种潜在的IBD治疗方法。
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)
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Fayez Khalaf Ghishan其他文献
Fayez Khalaf Ghishan的其他文献
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{{ truncateString('Fayez Khalaf Ghishan', 18)}}的其他基金
Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis
钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用
- 批准号:
9402244 - 财政年份:2017
- 资助金额:
$ 61.55万 - 项目类别:
Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis
钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用
- 批准号:
9980395 - 财政年份:2017
- 资助金额:
$ 61.55万 - 项目类别:
Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases
炎症性肠病发病机制中树突状细胞功能的调节
- 批准号:
9349503 - 财政年份:2016
- 资助金额:
$ 61.55万 - 项目类别:
Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases
炎症性肠病发病机制中树突状细胞功能的调节
- 批准号:
9754114 - 财政年份:2016
- 资助金额:
$ 61.55万 - 项目类别:
Summers in Children's Research for Diverse High School Students
不同高中生的儿童研究暑期活动
- 批准号:
10610857 - 财政年份:2013
- 资助金额:
$ 61.55万 - 项目类别:
Summers in Children's Research for Diverse High School Students
不同高中生的儿童研究暑期活动
- 批准号:
10383164 - 财政年份:2013
- 资助金额:
$ 61.55万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
8332260 - 财政年份:2006
- 资助金额:
$ 61.55万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
8913142 - 财政年份:2006
- 资助金额:
$ 61.55万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
7657335 - 财政年份:2006
- 资助金额:
$ 61.55万 - 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
- 批准号:
7268715 - 财政年份:2006
- 资助金额:
$ 61.55万 - 项目类别: