Anti-arthritic activity and therapeutic use of novel joint-homing peptides

新型关节归巢肽的抗关节炎活性和治疗用途

• 批准号: 9339552
• 负责人: KAMAL D MOUDGIL
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339552
• 关键词: Address; Adjuvant Arthritis; Adverse effects; Adverse reactions; Affect; Aging; American; Aminopeptidase P; Antibodies; Antigen Targeting; Arginine; Arthritis; Aspartic Acid; Attenuated; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; Bacteriophages; Binding; Blood Circulation; Blood Vessels; Cells; Characteristics; Chronic; Code; Collaborations; Comparative Study; Cyclic Peptides; Detection; Development; Disease; Drug Delivery Systems; Drug Targeting; Drug toxicity; Encapsulated; Endothelial Cells; Endothelium; Event; Experimental Models; Gene Expression Profile; Glucosephosphate Isomerase; Glycine; Goals; Health; Health Care Costs; Healthcare; Heat shock proteins; Heterogeneity; Home environment; Homing; Human; Immunity; In Vitro; Individual; Inflammation; Inflammation Mediators; Injectable; Institutes; Integrins; Intra-Articular Injections; Joints; Knowledge; Leukocytes; Ligand Binding; Liposomes; Mediator of activation protein; Medical Research; Methodology; Methods; Military Personnel; Modeling; Molecular; Organ; Organ Specificity; Pain; Pathogenesis; Pathogenicity; Pathologic; Peptide Phage Display Library; Peptides; Phage Display; Pharmaceutical Preparations; Poison; Polyethylene Glycols; Population; Prevalence; Process; Proteins; Publishing; Quality of life; RGD (sequence); Rat-1; Rattus; Receptor Cell; Rehabilitation therapy; Reporting; Research Institute; Research Personnel; Reticuloendothelial System; Rheumatoid Arthritis; Series; Signal Transduction; Stress; Surface; Synovitis; System; T-Lymphocyte; Therapeutic Agents; Therapeutic Effect; Therapeutic Index; Therapeutic Uses; Time; Tissues; Vascular Endothelial Cell; Vascular Endothelium; Vesicle; Veterans; Wit; Woman; Work; alanine aminopeptidase; antiarthritic agent; arthropathies; autoimmune arthritis; base; bone; cell motility; combat; design; disability; experience; in vivo; innovation; insight; joint injury; men; migration; molecular marker; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; public health relevance; receptor binding; systemic autoimmune disease; systemic toxicity; targeted delivery; treatment strategy; tumor; uptake

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic debilitating disease affecting over 1% of Americans. Women are affected about 3 times more often than men. RA also constitutes a major health problem among the U.S. Veterans. The Veteran population is aging, and the number of women serving in the military is gradually increasing. In addition, Veterans in combat zones are exposed to extreme stress and toxic substances in different forms. All these factors may directly or indirectly influence host immunity and induction/aggravation of RA. The pain, discomfort, lost working days, and disabilities caused by RA can adversely affect Veterans' quality of life and work in many ways, as well as impose heavy cost of healthcare and rehabilitation. Therefore, studies advancing our understanding of the pathogenesis and treatment of RA are highly relevant to the U.S. Veterans. Two main challenges in the field of arthritis are 1) to define the mechanisms that render the joints highly prone to attack by a systemic autoimmune response, and 2) to devise novel ways to direct systemically-administered drugs primarily into the inflamed joints (without intra-articular injection) to achieve maximum therapeutic effect, but with minimum adverse effects. We hypothesize that the vascular endothelium of the inflamed joints is characterized by unique molecular markers that facilitate both selective migration of pathogenic T cells into the target organ (the arthritic joints) and cellular/ molecular interactions with the mediators of inflammation and bone damage. Furthermore, the targeting of one or more of these vascular endothelial cell markers would offer new therapeutic approaches for downregulating joint inflammation and tissue damage without undue adverse reactions or systemic toxicity. This proposition is based on the results of our recently published study in PNAS on the synovial vasculature in the rat adjuvant arthritis (AA) model of RA, which was done in collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham Institute, La Jolla, CA). The study was aimed at identifying unique arthritic joint-homing peptides using an innovative approach of in vitro and in vivo enrichment of clones from a phage peptide-display library. The advantage of the phage system for the detection of tissue-specific markers is that there is no a priori bias in predicting the ligands that bind to the vascular endothelium. And, unlike antibodies the phage-displayed peptides interact with the functional domain of the target molecule. This approach has been pioneered by Dr. Ruoslahti, who has developed the concept of vascular "address molecules" or "zip codes." His group has examined several organs in this regard, but not the joints. We have now filled this gap by identifying two novel 9-residue peptides (denoted as NQR and ADK) that preferentially home to the inflamed joints and show unique receptor-binding and cellular-signaling attributes compared to the well-known arginine-glycine-aspartic acid (RGD) motif that binds to specific integrins. Furthermore, the treatment of arthritic rats wit NQR peptide attenuated AA, whereas ADK peptide failed to do so. The aims of our study are: Aim 1. Use the peptides (NQR and ADK) with a drug for synovial vasculature-targeted delivery into arthritic joints to control inflammation and bone damage. As a proof-of-concept, the drug will be encapsulated in liposomes, whose surface is decorated with NQR/ADK peptide. These joint-homing peptides would direct the liposomes preferentially into the inflamed joints. Liposomes will be treated with polyethylene glycol to inhibit their uptake by the reticuloendothelial system; Aim 2. Define the cellular/molecular events triggered by the joint-homing peptides upon interaction with endothelial cells and to examine the mechanisms underlying the anti-arthritic activity of NQR peptide. We will determine the effect of NQR/ADK peptide on the pathogenic mediators produced by endothelial cells; the gene expression profile of endothelial cells; and the migration of defined subsets of leukocytes. The results of this study would advance our knowledge of the disease process in autoimmune arthritis and help design novel peptide-directed, targeted drug delivery with increased therapeutic index for the treatment of RA.

描述（由申请人提供）： 类风湿性关节炎 (RA) 是一种慢性衰弱性疾病，影响超过 1% 的美国人。女性受影响的几率是男性的 3 倍左右。类风湿性关节炎也是美国退伍军人的一个主要健康问题。退伍军人人口正在老龄化，女性在军队服役的人数正在逐渐增加。此外，战区的退伍军人还面临着极端的压力和不同形式的有毒物质。这些因素都可能直接或间接影响宿主免疫和RA的诱发/加重。 RA 引起的疼痛、不适、工作日损失和残疾会在很多方面对退伍军人的生活和工作质量产生不利影响，并带来高昂的医疗和康复费用。因此，促进我们对 RA 发病机制和治疗的理解的研究与美国退伍军人高度相关。关节炎领域的两个主要挑战是：1）确定使关节极易受到全身性自身免疫反应攻击的机制；2）设计新方法，将全身给药的药物主要引导至发炎关节（无需关节内注射），以达到最大的治疗效果，同时将不良反应降至最低。我们假设发炎关节的血管内皮具有独特的分子标记，这些标记既促进致病性 T 细胞选择性迁移到靶器官（关节炎关节），又促进细胞/分子与炎症和骨损伤介质的相互作用。此外，靶向一种或多种这些血管内皮细胞标记物将为下调关节炎症和组织损伤提供新的治疗方法，而不会产生过度的不良反应或全身毒性。这一主张基于我们最近在 PNAS 上发表的关于 RA 大鼠佐剂性关节炎 (AA) 模型滑膜脉管系统的研究结果，该研究是与 Erkki Ruoslahti 博士（加利福尼亚州拉霍亚桑福德-伯纳姆研究所）合作完成的。该研究旨在利用噬菌体肽展示库中克隆的体外和体内富集创新方法来鉴定独特的关节炎关节归巢肽。噬菌体系统用于检测组织特异性标记物的优点是在预测与血管内皮结合的配体时不存在先验偏差。而且，与抗体不同的是，噬菌体展示的肽与目标分子的功能域相互作用。这种方法是由 Ruoslahti 博士首创的，他提出了血管“地址分子”或“邮政编码”的概念。他的小组在这方面检查了多个器官，但没有检查关节。现在，我们通过鉴定两种新型 9 残基肽（表示为 NQR 和 ADK）填补了这一空白，它们优先归巢于发炎关节，与众所周知的与特定整合素结合的精氨酸-甘氨酸-天冬氨酸 (RGD) 基序相比，它们显示出独特的受体结合和细胞信号传导属性。此外，用 NQR 肽治疗关节炎大鼠可减弱 AA，而 ADK 肽则不能。我们研究的目的是： 目的 1. 将肽（NQR 和 ADK）与药物一起使用，将滑膜脉管系统靶向递送至关节炎关节，以控制炎症和骨损伤。作为概念验证，该药物将 封装在脂质体中，脂质体表面用 NQR/ADK 肽修饰。这些关节归巢肽将优先引导脂质体进入发炎的关节。脂质体将用聚乙二醇处理，以抑制网状内皮系统对其的摄取； 目标 2. 定义关节归巢肽与内皮细胞相互作用时触发的细胞/分子事件，并检查 NQR 肽抗关节炎活性的机制。我们将确定NQR/ADK肽对内皮细胞产生的致病介质的影响；内皮细胞的基因表达谱；以及特定白细胞亚群的迁移。这项研究的结果将增进我们对自身免疫性关节炎疾病过程的了解，并有助于设计新型肽导向的靶向药物递送，提高治疗 RA 的治疗指数。