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：
Fayez Khalaf Ghishan
金额：
$ 61.55万
依托单位：
UNIVERSITY OF ARIZONA
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：
https://reporter.nih.gov/project-details/10679646
关键词：
ADP ribosylation Adenosine Diphosphate Ribose Affect Amino Acids Biology Caring Cell Compartmentation Cell physiology Cellular biology Chronic Clinical Coenzyme A Colitis Colon Colonic inflammation Complex DNA Repair Enzymes Data Disease Disease Progression Energy Metabolism Epithelial Cells Epithelium Etiology FDA approved Genetic Transcription Germ-Free Gut Mucosa Homeostasis Human Hyperactivity Immune response Immune system Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injury Knock-out Maintenance Marketing Mediating Metabolic Microbe Mind Modeling Mucositis Mucous Membrane Mus Onset of illness Outcome Pathogenesis Patients Play Poly(ADP-ribose) Polymerases Polymerase Post-Translational Protein Processing Predisposition Proteins Recovery Regulatory T-Lymphocyte Relapse Research Risk Role Sirtuins Structure Supplementation System Testing Time Work anti aging bacterial community candidate identification cofactor commensal bacteria commensal microbes comparative design efficacy evaluation fecal transplantation gastrointestinal gastrointestinal epithelium gut inflammation gut microbiota host microbiome improved in vivo inhibitor large bowel Crohn&apos s disease microbial community microbial composition microbiome alteration microbiota murine colitis nicotinamide-beta-riboside novel novel strategies oral supplementation pharmacologic protein function public health relevance targeted 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望而生畏，并且仍未完全了解。在本提案中，我们表明聚 ADP-核糖基化。 (PARylation) 是一种翻译后修饰，涉及 ADP-核糖 (ADPr) 从 NAD+ 酶促转移到目标蛋白的特定氨基酸，作为我们首次提供证据表明 PARP1 是结肠中的主要 PAR 书写者，它是粘膜 PARP1 活性和 PARylation 所必需的共生细菌。 PARP1 控制微生物组成和代谢活动，调节结肠上皮屏障功能，并限制粘膜 Treg 区室。与粘膜过度PARylation相关，可以将其转移到来自IBD患者的具有复杂微生物群落的无菌小鼠中。，我们发现，过度PARylation是通过结肠中的外在（与肠道微生物群相互作用）和内在作用导致粘膜炎症和粘膜恢复受损的重要因素。我们将在以下三个整合良好但不是相互关联的具体目标中解决这一假设，这些目标将： (1) 定义 NAD+ 耗竭与过度 PARylation 在实验性结肠炎发病机制中的假定罪魁祸首的作用 (2) 定义PARP1 和 PARylation 在人类 IBD 微生物群介导的结肠炎中的作用；(3) 从机制上定义 PARP1 在肠道之间高度相互作用的关系中的作用；发炎结肠中的微生物群和上皮屏障功能以及粘膜恢复。这项新颖的研究计划将极大地推进基础粘膜生物学领域，并将提供针对 PARP1 活性的潜在 IBD 治疗。