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.
尽管最近在了解炎症性肠病(IBD)发病机制中宿主-微生物组相互作用方面取得了进展,但宿主对肠道微生物群变化的反应的复杂性令人生畏,并且仍然没有完全了解。在本研究中,我们发现多adp核糖基化(PARylation)是一种翻译后修饰,涉及adp核糖(ADPr)从NAD+酶转移到靶蛋白的特定氨基酸,在肠道炎症反应中起关键作用。我们首次提供证据证明PARP1是结肠中主要的PAR撰写者,在结肠中它是一种强大的转录调节剂。共生菌是粘膜PARP1活性和PARP1修饰所必需的,反过来,PARP1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室。重要的是,人类和小鼠结肠炎与粘膜高parylation相关,这可以从IBD患者转移到具有复杂微生物群落的无菌小鼠。PARP1的完全或上皮特异性敲除(或药理学抑制)可以保护和促进粘膜损伤的恢复。基于这些新颖的初步观察结果,我们假设高parylation是通过结肠粘膜的外在(与肠道微生物群的相互作用)和内在作用导致粘膜炎症和粘膜修复受损的重要因素。我们将通过以下三个整合良好但并非相互偶然的具体目标来解决这一假设,这将:(1)确定NAD+缺失与高PARylation在实验性结肠炎发病机制中的作用(2)确定PARP1和PARylation在人类IBD微生物群介导的结肠炎中的作用;(3)从机制上确定PARP1在肠道微生物群与上皮屏障功能和粘膜恢复之间的高度互动关系中的作用。在发炎的结肠里。这一新颖的研究计划将极大地推动基础粘膜生物学领域的发展,并将提供靶向PARP1活性作为潜在的IBD治疗方法。
项目成果
期刊论文数量(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: