The pathogenic role of poly (ADP-ribose) polymerase 1 (PARP-1) in experimental co

聚（ADP-核糖）聚合酶1（PARP-1）在实验co中的致病作用

基本信息

批准号：
8685976
负责人：
Claire Larmonier
金额：
$ 11.49万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685976
关键词：
ADP ribosylation Ablation Address Adenosine Diphosphate Ribose Affect Animal Model Biological Biology Bone Marrow Cell Adhesion Cell Adhesion Molecules Cell Cycle Regulation Cell Death Cells Chemotaxis Chimera organism Chromatin Structure Colitis Colorectal Cancer Complement Complex DNA Repair DNA-Binding Proteins Data Development Dextran Sulfate Diabetes Mellitus Disease Disease remission Drug Kinetics Enzymes Epithelial Epithelial Cells Family Foundations Funding Future Gene Expression Genetic Hematopoietic Immune Immune response Immune system Immunosuppressive Agents In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Injury Intestines Knock-out Knockout Mice Laboratories Light Literature Malignant Epithelial Cell Mediating Mediator of activation protein Modeling Modification Mucosal Immune Responses Mus NF-kappa B Osteoblasts Outcome Patients Pattern Permeability Pharmacodynamics Pharmacologic Substance Physiological Processes Play Poly(ADP-ribose) Polymerases Predisposition Process Protein Isoforms Proteins Publishing Rag1 Mouse Regulation Reperfusion Injury Research Research Project Grants Role Septic Shock Signal Pathway Signal Transduction Stimulus Streptomycin T-Lymphocyte Testing Therapeutic Tight Junctions Tissues Transcription Factor AP-1 United States National Institutes of Health base cell type chemokine cofactor cytokine design driving force improved in vivo in vivo Model inflammatory modulation insight macrophage member migration mouse model neutrophil novel overexpression preclinical study protein expression public health relevance reconstitution repaired response therapeutic target transcription factor translational study

项目摘要

DESCRIPTION (provided by applicant): Poly (ADP-ribose) polymerases (PARPs) constitute a family of 18 cell signaling enzymes, which are involved in the regulation of DNA-binding proteins and DNA repair. These enzymes catalyze the transfer of ADP-ribose units from NAD+ to a number of acceptor proteins (by a process called poly (ADP) ribosylation) and can also interact directly with their target proteins. Among the PARPs, PARP1 is the most abundant isoform and has been described to regulate the expression of diverse proinflammatory mediators, through its interaction with numerous transcription factors such as NF-kB and AP-1. Recent published observations (including our group) suggest that PARP-1 is a cofactor for NF-kB-dependent gene expression. Several studies in Parp1 KO mice have shown a decreased expression of host inflammatory mediators, cytokines, chemokines, adhesion molecules as well as reduced immune tissue infiltration in various model of inflammation including, streptomycin induced diabetes, LPS induced septic shock, ischemia and reperfusion injury. Interestingly, in vivo studies have demonstrated that genetic ablation or pharmacological inhibition of PARP1 ameliorates the pathophysiological changes of experimental colitis. However, the studies published to date have failed to characterize the exact mechanism by which PARP1 inhibition is protective in colitis and in which cell type PARP1 inhibition would have the most significant impact in IBD. Such studies are critical in guiding future development of therapeutics targeting PARP1, with proper pharmacokinetics and pharmacodynamics. Our preliminary data obtained with adoptive T-cell transfer model of colitis indicate that Parp1 is dispensable in T-cells, while Parp1-/- mice are protected from colitis resulting from epithelial damage induced by DSS. These data collectively suggests that the pathogenic role of Parp1 in colitis is restricted to either colonic epithelial cells or other cells of the innate immune system. A novel mouse model for conditional cell-type specific Parp1 targeting, Parp1/Rag1 double knockout mice, and bone marrow chimeras developed as part of this proposal will be used in the following specific aims: (1) we are planning to differentiate the pathogenic role of PARP1 in hematopoietic or parenchymal cells in the development of colitis, (2) to investigate the role of Parp1 deletion in intestinal epithelial cells and (3) to characterize the role of PARP1 on neutrophil and macrophage functions. Those specific aims will help address the following hypothesis: PARP1 contributes to aggravated mucosal immune response via modulation of inflammatory signaling pathways within the cells of the innate immune system.

描述（由申请人提供）：聚（ADP-核糖）聚合酶（PARP）构成18种细胞信号转导酶的家族，其参与DNA结合蛋白和DNA修复的调节。这些酶催化 ADP-核糖单位从 NAD+ 转移到许多受体蛋白（通过称为聚 (ADP) 核糖基化的过程），并且还可以直接与其靶蛋白相互作用。在 PARP 中，PARP1 是最丰富的异构体，并且已被描述为通过与多种转录因子（如 NF-kB 和 AP-1）相互作用来调节多种促炎介质的表达。最近发表的观察结果（包括我们的小组）表明 PARP-1 是 NF-kB 依赖性基因表达的辅助因子。对 Parp1 KO 小鼠的几项研究表明，在各种炎症模型中，包括链霉素诱导的糖尿病、LPS 诱导的感染性休克、缺血和再灌注损伤，宿主炎症介质、细胞因子、趋化因子、粘附分子的表达降低，免疫组织浸润减少。有趣的是，体内研究表明，PARP1 的基因消除或药理抑制可改善实验性结肠炎的病理生理变化。然而，迄今为止发表的研究未能描述 PARP1 抑制在结肠炎中发挥保护作用的确切机制，以及哪种细胞类型 PARP1 抑制对 IBD 具有最显着的影响。此类研究对于指导未来开发针对 PARP1 的疗法以及适当的药代动力学和药效学至关重要。我们通过结肠炎过继性 T 细胞转移模型获得的初步数据表明 Parp1 在 T 细胞中是可有可无的，而 Parp1-/- 小鼠免受 DSS 诱导的上皮损伤引起的结肠炎。这些数据共同表明 Parp1 在结肠炎中的致病作用仅限于结肠上皮细胞或先天免疫系统的其他细胞。作为本提案的一部分开发的一种用于条件细胞类型特异性 Parp1 靶向的新型小鼠模型、Parp1/Rag1 双敲除小鼠和骨髓嵌合体将用于以下具体目标：（1）我们计划区分致病作用造血细胞或实质细胞中 PARP1 在结肠炎发生过程中的作用，(2) 研究 Parp1 缺失在肠上皮细胞中的作用，(3) 表征 PARP1 在结肠炎发生过程中的作用中性粒细胞和巨噬细胞的功能。这些具体目标将有助于解决以下假设：PARP1 通过调节先天免疫系统细胞内的炎症信号通路而加剧粘膜免疫反应。