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: 8638421
• 负责人: KAMAL D MOUDGIL
• 金额: $ 23.03万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638421
• 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; 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; public health relevance; receptor binding; screening; trafficking; treatment strategy

PROJECT SUMMARY 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. .

项目摘要 多发性硬化症（MS）是一种慢性衰弱性自身免疫性疾病，涉及炎症和损伤， 中枢神经系统（CNS）。多种自身抗原，包括髓鞘少突胶质细胞糖蛋白 (MOG)、蛋白脂质蛋白（PLP）和髓鞘碱性蛋白（MBP）参与了 女士对这些抗原有反应性的T细胞通过血脑屏障进入CNS， 炎症和组织损伤。在MS领域工作的研究人员面临的两个主要挑战是- 1)确定使CNS高度倾向于自身免疫攻击的潜在机制，以及2） 设计新的方法来引导口服或注射药物主要进入中枢神经系统，以增强其 有效性，同时最大限度地减少不良影响。我们假设中枢神经系统的血管内皮细胞 其特征在于独特的分子标志物，其促进致病性T细胞选择性迁移到 靶器官（CNS）以及与炎症诱导物/介质的细胞相互作用， 组织损伤与Erkki Ruoslahti博士（加利福尼亚州拉霍亚的桑福德-伯纳姆研究所）合作，我们 最近完成并发表的（PNAS 2011，108：12857）大鼠滑膜脉管系统的研究 佐剂性关节炎模型。该研究的目的是使用以下方法识别独特的关节特异性血管标记物： 一种从噬菌体肽展示文库中体内富集克隆的创新方法。的优点 用于检测组织特异性标志物的噬菌体系统在预测配体时没有先验偏差 在血管内皮中。此外，与抗体不同，噬菌体展示肽与抗体相互作用。 靶分子的功能结构域。这种方法是由Ruoslahti博士开创的，他 发展了血管“地址分子”或“邮编”的概念。他的团队和其他调查人员 在这方面检查了几个器官，除了发炎的中枢神经系统。我们假设血管 EAE中脑和脊髓的内皮细胞的特征在于独特的分子标记物， 通过这些标记物中的一种或多种靶向药物将下调炎症和组织损伤， 中枢神经系统无不良反应或全身毒性。本研究的目的是基于MOG-EAE， PLP-EAE模型（与Ruoslahti博士和EAE专家-Scott博士和Lees博士合作） 目的：1、鉴定小鼠炎症中枢神经系统血管内皮的独特“地址分子 用EAE体内筛选噬菌体肽库的方法。目标2，使用CNS导引 用于将血管靶向药物递送到CNS炎症和组织损伤部位的肽。我们认为 本研究的结果将促进我们对EAE/MS发病机制的理解，并为EAE/MS的研究奠定基础。 通过转化研究为MS设计新的肽导向疗法的方法。 .