Progranulin Intervention in Inflammatory Bowel Diseases

颗粒体蛋白前体干预炎症性肠病

• 批准号: 8708276
• 负责人: Chuanju Liu
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708276
• 关键词: Adoptive Transfer; Adverse effects; Affect; Animal Model; Ankylosing spondylitis; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Attenuated; Autoimmune Process; Cells; Chronic; Chronic small plaque psoriasis; Colitis; Colon; Crohn' s disease; Development; Disease; Down-Regulation; Engineering; Etanercept; Event; Exhibits; Fluorescence; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genetic; Genetic Screening; Goals; Growth Factor; Human; Immune; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intervention; Intestines; Investigation; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Ligands; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Monitor; Mucous Membrane; Mus; PGRN gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Production; Progranulin; Property; Protein Engineering; Psoriatic Arthritis; Reaction; Recombinants; Regulatory T-Lymphocyte; Relapse; Reporter; Reporting; Research; Rheumatoid Arthritis; Role; Signal Transduction; Sodium Dextran Sulfate; Swelling; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; TNFRSF1A gene; TNFRSF1B gene; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tigers; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Ulcerative Colitis; alternative treatment; cancer risk; cell fixing; cost; cytokine; in vivo; infliximab; inhibitor/antagonist; insight; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; protective effect; response

DESCRIPTION (provided by applicant): Ulcerative colitis and Crohn's disease are chronic, relapsing inflammatory disorders of the gastrointestinal tract, collectively known as Inflammatory Bowel Disease (IBD). The cause of IBD, which in the U.S. affects an estimated 1.4 million individuals, remains largely unknown. Pro-inflammatory cytokines are believed to play important roles in the pathogenesis of IBD. Among these cytokines, tumor necrosis factor (TNF) has received the greatest attention because of its position at the apex of the inflammatory and immune-regulatory cascades. TNF inhibitors, such as Remicade and Enbrel, have been accepted as an effective approach to treating various kinds of inflammatory diseases, including Crohn's disease and ulcerative colitis. However, their side effects and high cost prompt investigations into new, alternative treatment modalities. One such alternative is a long- known anti-inflammatory growth factor, progranulin (PGRN), which was only recently discovered to be a novel ligand of TNF receptors (TNFR) in our global genetic screen. We recently reported that PGRN antagonizes TNF activity and significantly attenuates or ameliorates experimentally induced inflammatory arthritis in mice. More importantly, Atsttrin, an engineered protein composed of three PGRN fragments, exhibited highly potent anti-inflammatory activity, which surpassed PGRN itself, in vivo. Using PGRN deficient mice, we demonstrated in our preliminary studies that the deletion of the PGRN gene renders B6 mice more susceptible to Dextran Sulfate Sodium (DSS) induction and to developing more severe colitis. In addition, PGRN antagonizes TNF¿- mediated down-regulation of Treg suppressive function and Foxp3 expression; in vivo treatment with PGRN selectively stimulates IL-10 production in Treg cells and PGRN-stimulated Treg suppressive function is largely lost if IL-10 signaling is blocked. These studies have led to the central hypothesis that PGRN exerts its protective effects through its interaction with TNFR and the stimulation of IL-10 producing Treg cells in the course of inflammatory bowel disease. This hypothesis will be tested in three Specific Aims: (1) Do PGRN-mediated signaling and molecular events depend on PGRN's interaction with TNF/TNFR in Tregs and in inflammatory bowel disease? (2) Is IL-10 a critical mediator of PGRN action in the pathogenesis of inflammatory bowel disease? (3) Can recombinant PGRN, especially its derived Atsttrin, be directly applied to treat inflammatory bowel disease? Successful completion of the proposed research will not only benefit our understanding of the pathogenesis of IBD, but also lead to the development of new anti-TNF/TNFR therapeutic interventions for various kinds of TNF-related diseases, including IBD. .

描述(申请人提供)：溃疡性结肠炎和克罗恩病是一种慢性、复发性胃肠道炎症性疾病，统称为炎症性肠病(IBD)。IBD的病因在很大程度上仍不清楚。据估计，美国有140万人患有IBD。促炎细胞因子被认为在IBD的发病机制中起重要作用。在这些细胞因子中，肿瘤坏死因子(TNF)因其处于炎症和免疫调节通路的顶端而受到最大的关注。肿瘤坏死因子抑制剂，如Remicade和Enbrel，已被认为是治疗各种炎症性疾病的有效方法，包括克罗恩病和溃疡性结肠炎。然而，它们的副作用和高昂的成本促使人们研究新的替代治疗方式。其中一种替代方案是一种已知已久的抗炎生长因子原颗粒(PGRN)，它是最近才在我们的全球遗传筛查中发现的一种新的肿瘤坏死因子受体(TNFR)配体。我们最近报道了PGRN拮抗肿瘤坏死因子活性，并显著减轻或改善实验诱导的小鼠炎性关节炎。更重要的是，由三个PGRN片段组成的工程蛋白Atsttrin在体内显示出超过PGRN本身的高效抗炎活性。利用PGRN缺陷小鼠，我们在初步研究中证明，PGRN基因的缺失使B6小鼠更容易受到葡聚糖硫酸钠(DSS)的诱导，并患上更严重的结肠炎。此外，PGRN可拮抗肿瘤坏死因子介导的Treg抑制功能和Foxp3表达的下调；在体内，PGRN选择性地刺激Treg细胞产生IL-10，如果IL-10信号转导被阻断，则PGRN刺激的Treg抑制功能将大大丧失。这些研究导致了一个中心假设，即在炎症性肠病过程中，PGRN通过与TNFR相互作用和刺激产生IL-10的Treg细胞来发挥其保护作用。这一假说将在三个特定的目标下得到验证：(1)PGRN介导的信号和分子事件是否依赖于PGRN在Tregs和炎症性肠病中与肿瘤坏死因子/肿瘤坏死因子受体的相互作用？(2)IL-10是PGRN在炎症性肠病发病机制中作用的关键介质吗？(3)重组PGRN，特别是其衍生的Atsttrin，能否直接用于治疗炎症性肠病？本研究的成功完成不仅有助于我们对IBD发病机制的认识，还将为包括IBD在内的各种肿瘤坏死因子相关疾病的治疗提供新的治疗手段。。