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: 8998611
• 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/8998611
• 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 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 Mediators; 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; Osteitis; Pain; Pathogenesis; 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; Rehabilitation therapy; Reporting; Research Institute; Research Personnel; Reticuloendothelial System; Rheumatoid Arthritis; Series; Signal Transduction; Stress; Surface; Swelling; 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; combat; design; disability; experience; in vivo; innovation; insight; joint injury; men; migration; molecular marker; neoplastic cell; novel; novel therapeutic intervention; receptor; 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)： 类风湿关节炎(RA)是一种慢性衰弱疾病，影响着超过1%的美国人。女性受到影响的频率大约是男性的3倍。RA也构成了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，在军队服役的女性人数正在逐渐增加。此外，战区退伍军人面临着不同形式的极端压力和有毒物质。这些因素可能直接或间接影响宿主免疫和RA的诱发/加重。RA造成的疼痛、不适、工作日损失和残疾会在许多方面对退伍军人的生活和工作质量产生不利影响，并带来沉重的医疗和康复成本。因此，促进我们对RA发病机制和治疗的了解的研究对美国退伍军人具有高度的相关性。关节炎领域的两个主要挑战是1)确定使关节高度容易受到全身自身免疫反应攻击的机制，2)设计新的方法，将系统给药主要定向到发炎的关节(不需要关节内注射)，以达到最大的治疗效果，但副作用最小。我们假设炎症关节的血管内皮细胞具有独特的分子标志物，促进致病T细胞选择性地迁移到靶器官(关节炎关节)，以及与炎症和骨损伤的介质的细胞/分子相互作用。此外，靶向这些血管内皮细胞标记物中的一个或多个将为降低关节炎症和组织损伤提供新的治疗方法，而不会出现不必要的不良反应或全身毒性。这一命题是基于我们最近在PNAS上发表的关于RA大鼠佐剂性关节炎(AA)模型中滑膜血管系统的研究结果，该研究是与加利福尼亚州拉霍亚的Sanford-Burnham研究所的Erkki Ruola hti博士合作完成的。这项研究的目的是利用一种从噬菌体展示多肽文库中体外和体内富集克隆的创新方法来鉴定独特的关节炎关节归巢多肽。噬菌体系统用于检测组织特异性标记物的优势在于，在预测与血管内皮细胞结合的配体时没有先验偏差。而且，与抗体不同的是，噬菌体展示的多肽与目标分子的功能域相互作用。这种方法是由鲁斯拉赫蒂博士率先提出的，他提出了血管“地址分子”或“邮政编码”的概念。他的团队在这方面检查了几个器官，但没有检查关节。我们现在已经通过鉴定两个新的9残基多肽(标记为NQR和ADK)填补了这一空白，它们优先定位于炎症关节，并显示出独特的受体结合和细胞信号属性，而不是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。此外，用NQR肽治疗关节炎大鼠可使AA减弱，而ADK肽不能降低AA。本研究的目的是：1.将NQR和ADK这两种多肽与一种滑膜血管靶向给药一起应用于关节炎关节，以控制炎症和骨损伤。作为一种概念验证，这种药物将 被包裹在脂质体中，其表面修饰有NQR/ADK多肽。这些关节归巢多肽将引导脂质体优先进入发炎的关节。脂质体将用聚乙二醇处理，以抑制其被网状内皮系统摄取； 目的2.明确关节归巢多肽与血管内皮细胞相互作用所引发的细胞/分子事件，探讨NQR多肽抗关节炎作用的机制。我们将确定NQR/ADK多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；以及确定的白细胞亚群的迁移。这项研究的结果将促进我们对自身免疫性关节炎的疾病过程的了解，并有助于设计具有更高治疗指数的新型多肽导向、靶向给药治疗类风湿关节炎。