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Multifunctional Biomaterial for Amelioration of MS in Murine EAE Model

用于改善小鼠 EAE 模型 MS 的多功能生物材料

基本信息

批准号：
8893453
负责人：
JULIA E BABENSEE
金额：
$ 21.02万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893453
关键词：
Address Adult Anti-Inflammatory Agents Anti-inflammatory Antigens Attenuated Autoimmune Diseases Autoimmune Process Autoimmunity Biocompatible Materials Brain Cell Adhesion Cell Survival Cells Cervical lymph node group Cessation of life Chronic Demyelinations Dendritic Cell Therapy Dendritic Cells Disease Disease Outcome Drug Formulations Effectiveness Experimental Autoimmune Encephalomyelitis Gel Gelatin Glucose Goals Human Hydrogels Immunosuppressive Agents Implant In Situ In Vitro Inflammation Inflammatory Injectable Interleukin-10 Ischemia Lesion Location Mediating Microglia Modeling Multiple Sclerosis Mus Myelin Myelin Sheath Neck Nerve Degeneration Neuraxis Neuregulin 1 Neurologic Neurons Neuroprotective Agents Oxygen Phenotype Polyethylene Glycols Process RGD (sequence)Research Signal Transduction Site Spinal Cord Surface Symptoms System T-Lymphocyte Therapeutic Translating Validation Work attenuation autocrine axon injury base central nervous system injury combat conditioning controlled release crosslink deprivation design disability immunoregulation in vitro Model innovation neuroprotection prophylactic public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune disease causing neurological deficits associated with inflammation- mediated damage to myelin sheaths covering brain and spinal cord neurons. Axonal damage is now believed to occur early in the disease course, in every new lesion, with progressive and irreversible disability arising from cumulative axonal loss. The autoimmune attack on the central nervous system (CNS) in MS has been suggested to be a secondary pathogenic factor evoked by CNS injury. Autoimmunity against myelin antigens further exacerbates the autocatalytic process of neurodegeneration. The approach proposed herein aims to combine the two necessary components of MS therapeutic approaches into a single strategy addressing the dendritic cell (DC) phenotype imbalance and promotion of neuroprotection. The overall goal is elucidate the biomaterial and immunological basis of a biomaterial strategy for immunomodulation through MS-antigen specific immunosuppressive DC delivery within a polyethylene glycol (PEG) hydrogel and combined with delivery of the neuroprotective factor, neuregulin-1 (NRG-1), to ameliorate the murine experimental autoimmune encephalomyelitis (EAE) model of MS. The hypothesis for this research is that DCs, rendered antigen specific and tolerogenic by contact with an MS antigen upon immunosuppressive molecule treatment in vitro, can be applied to the cervical lymph nodes (cLNs), using a localized hydrogel system, along with release of the neuroprotective agent, NRG-1, to ameliorate EAE disease outcomes through immunomodulation and neuroprotection. In this study, a simplified biomaterial strategy, with demonstrated efficacy as described in the preliminary results, is based on the delivery of immunosuppressive MS antigen-specific murine DCs to the neck location of mice within an in situ gelling PEG hydrogel, minimally modified to present the cell adhesion peptide, RGD. Two specific aims are proposed: 1) demonstrate functionality of critical components of the assembled multifunctional biomaterial for delivery of immunosuppressive, MS antigen-specific DCs and NRG-1; and 2) elucidate efficacy of the multifunctional biomaterial for amelioration of murine EAE through immunomodulation and neuroprotection and identify critical construct components.