PARP1 and PARylation as novel effectors of gut inflammation

PARP1 和 PARylation 作为肠道炎症的新型效应物

• 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
• 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' 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

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区系变化的反应的复杂性是令人望而生畏的，仍然不完全清楚。在这个建议中，我们证明了多聚ADP-核糖化(PARylation)是一种翻译后修饰，涉及ADP-核糖(ADPr)从NAD+到靶蛋白的特定氨基酸的酶转移，在肠道炎症反应中发挥关键作用。我们第一次提供了证据，证明PARP1是结肠中主要的PAR编写者，在结肠中它是一个强大的转录调节器。共生细菌是PARP1活性和PAR化所必需的，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间隔。重要的是，人和小鼠结肠炎与粘膜过度PAR化有关，这种高PAR化可以转移到IBD患者具有复杂微生物群落的无菌小鼠身上。完全或上皮特异性敲除PARP1(或药物抑制)可以保护和促进粘膜损伤的恢复。基于这些新的初步观察，我们假设高PAR化是通过结肠粘膜的外在(与肠道微生物区系相互作用)和内在作用而导致粘膜炎症和受损的粘膜修复的重要因素。我们将在以下三个整合良好但不相互偶然的特定目标中解决这一假说，这三个目标将：(1)定义NAD+耗竭和过度PAR化在实验性结肠炎发病中的可能罪魁祸首；(2)定义PARP1和PAR化在由人IBD微生物区系介导的结肠炎中的作用；以及(3)机械地定义PARP1在肠道微生物区系与上皮屏障功能和粘膜修复之间的高度互动关系中的作用。这一新的研究计划将极大地推动基础粘膜生物学领域的发展，并将提供针对PARP1活性的潜在IBD治疗方法。