Identification of CNS-homing peptides for therapeutic use in multiple sclerosis

鉴定用于治疗多发性硬化症的中枢神经系统归巢肽

• 批准号: 8897016
• 负责人: KAMAL D MOUDGIL
• 金额: $ 19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897016
• 关键词: Address; Adjuvant Arthritis; Adverse effects; Adverse reactions; Alanine; Animal Model; Antibodies; Antigens; Area; Arginine; Arthritis; Asparagine; Aspartic Acid; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteriophages; Binding; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Cells; Characteristics; Chronic; Clinical; Code; Collaborations; Detection; Development; Disease; Drug Delivery Systems; Drug Targeting; Encapsulated; Experimental Autoimmune Encephalomyelitis; Glutamine; Glycine; Health; Heterogeneity; Home environment; Homing; Human; Immune; Individual; Inflammation; Inflammation Mediators; Institutes; Integrins; Interferons; Joints; Leukocyte Trafficking; Libraries; Ligands; Liposomes; Lysine; Methodology; Methods; Mitoxantrone; Modeling; Multiple Sclerosis; Mus; Myelin Basic Proteins; Neuraxis; Normal tissue morphology; Organ; Paralysed; Pathogenesis; Pathology; Peptide Phage Display Library; Peptides; Phage Display; Pharmaceutical Preparations; Physiological; Play; Process; Proteins; Proteolipids; Publishing; RGD (sequence); Rattus; Reporting; Research Personnel; Role; SJL Mouse; Site; Spinal Cord; Study models; System; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Index; Therapeutic Uses; Tissues; Toxic effect; Translational Research; Tysabri; Vascular Endothelial Cell; Vascular Endothelium; Work; angiogenesis; autoreactive T cell; base; copolymer 1; design; disability; in vivo; innovation; insight; lymph nodes; migration; molecular marker; mouse myelin oligodendrocyte glycoprotein; natalizumab; neoplastic cell; novel; novel strategies; novel therapeutic intervention; oligodendrocyte-myelin glycoprotein; receptor binding; screening; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic debilitating autoimmune disease involving inflammation and damage to the central nervous system (CNS). A variety of autoantigens, including myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), and myelin basic protein (MBP) have been implicated in the pathogenesis of MS. The T cells reactive against these antigens access the CNS through the blood-brain barrier and cause inflammation and tissue damage. Two of the main challenges for researchers working in the field of MS are - 1) to define the underlying mechanisms that render the CNS highly prone to an autoimmune attack, and 2) to devise novel ways to direct the orally-administered or injected drugs primarily into the CNS to enhance their efficacy while minimizing adverse effects. We hypothesize that the vascular endothelium of the CNS is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ (the CNS) as well as cellular interaction with the inducers/mediators of inflammation and tissue damage. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham Institute at La Jolla, CA), we recently completed and published (PNAS 2011, 108: 12857) study of the synovial vasculature in the rat adjuvant arthritis model. The objective of that study was to identify unique joint-specific vascular markers using an innovative approach of in vivo enrichment of clones from a phage peptide-display library. The advantage of the phage system for detection of tissue-specific markers is that there is no a priori bias in predicting the ligand in the vascular endothelium. In addition, 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 and other investigators have examined several organs in this regard except the inflamed CNS. We hypothesize that the vascular endothelium of the brain and the spinal cord in EAE is characterized by unique molecular markers, and that the targeting of drugs via one or more of these markers would downregulate inflammation and tissue damage in the CNS without undue adverse reactions or systemic toxicity. The aims of our study based on MOG-EAE and PLP-EAE models (and in collaboration with Dr. Ruoslahti, and EAE experts- Drs. Scott and Lees) are as follows: Aim 1, to identify unique 'address molecules' for vascular endothelium of the inflamed CNS in mice with EAE using the in vivo screening of phage peptide-display library method. Aim 2, to use CNS-homing peptides for vasculature-targeted drug delivery into sites of CNS inflammation and tissue damage. We believe that the results of this study would advance our understanding of the pathogenesis of EAE/MS, and pave the way for designing novel peptide-directed therapeutics for MS through translational research.

描述(申请人提供)：多发性硬化症(MS)是一种慢性衰弱的自身免疫性疾病，涉及炎症和中枢神经系统(CNS)的损害。多种自身抗原，包括髓鞘少突胶质细胞糖蛋白(MOG)、蛋白脂蛋白(PLP)和髓鞘碱性蛋白(MBP)参与了MS的发病过程。与这些抗原反应的T细胞通过血脑屏障进入中枢神经系统，引起炎症和组织损伤。MS领域的研究人员面临的两个主要挑战是-1)确定使CNS高度容易受到自身免疫攻击的潜在机制，2)设计新的方法，将口服或注射的药物主要引导到CNS，以提高其疗效，同时将不良反应降至最低。我们假设中枢神经系统的血管内皮细胞具有独特的分子标记，这些分子标记促进致病T细胞选择性地迁移到靶器官(CNS)，以及细胞与炎症和组织损伤的诱导物/介导物的相互作用。我们最近与加州拉霍亚的桑福德-伯纳姆研究所的Erkki Ruola hti博士合作，完成并发表了(PNAS2011,108：12857)关于大鼠佐剂性关节炎模型中滑膜血管系统的研究。这项研究目的是确定独特的 使用一种创新的方法从噬菌体多肽展示文库中丰富克隆的关节特异性血管标记物。噬菌体系统用于检测组织特异性标志物的优势在于，在预测血管内皮细胞中的配体时没有先验偏见。此外，与抗体不同的是，噬菌体展示的多肽与靶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。他的团队和其他调查人员已经检查了这方面的几个器官，除了发炎的中枢神经系统。我们假设EAE患者脑和脊髓的血管内皮细胞具有独特的分子标志物，通过这些标志物中的一个或多个靶向药物将降低中枢神经系统的炎症和组织损伤，而不会出现不适当的不良反应或全身毒性。我们基于MOG-EAE和PLP-EAE模型的研究目的如下：目标1，利用噬菌体展示文库的体内筛选方法，确定EAE小鼠炎症中枢神经系统血管内皮细胞的独特地址分子。目的2，利用中枢神经系统归巢多肽向中枢神经系统炎症和组织损伤部位进行血管靶向给药。我们相信，本研究的结果将促进我们对EAE/MS发病机制的理解，并为通过翻译研究设计新型的多肽治疗MS铺平道路。