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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

基本信息

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
项目类别：
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

项目摘要

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. .

项目总结