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.

尽管了解炎症性肠病（IBD）中宿主微生物组相互作用的最新进展，但宿主对变化肠道微生物群的反应的复杂性令人生畏，但仍未完全理解。在该提案中，我们表明多-ADP-核糖基化（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，它在沟渠中扮演着关键的抗症状。我们第一次提供证据表明，PARP1是结肠中的主要PAR作者，它是强大的转录调节器。共生细菌对于粘膜PARP1活性和抚养性是必需的，并且相互控制，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 treg室。重要的是，人类和鼠结肠炎与粘膜过度确实能有关，可以将其转移到IBD患者的复杂微生物群落中的无菌小鼠中。 PARP1的总或上皮特异性敲除（或药物抑制）可防止并促进粘膜损伤的恢复。基于这些新颖的初步观察，我们假设过度毕业是通过外在（与肠道微生物群的相互作用）和结肠粘膜内在影响的粘膜感染和粘膜恢复受损的重要原因。我们将在以下三个良好整合但偶然的特定目的中解决这一假设，该目标将：（1）将NAD+定义与肥大性的作用定义为假定的罪魁祸首在实验性结肠炎的发病机理中（2）定义PARP1的作用，并定义了人类IBD Microbiota介导的COLPARITATION和PARYLATION中的作用。（3）机理上定义了PARP1在肠道菌群与上皮屏障功能和粘膜抑制之间的高度相互作用关系中的作用。在发炎的结肠中。这个新颖的研究计划将大大推进基本粘膜生物学领域，并将PARP1活性作为潜在的IBD疗法。