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

• 批准号: 9036386
• 负责人: JULIA E BABENSEE
• 金额: $ 22.14万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036386
• 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; Chronic; Demyelinations; Dendritic Cell Therapy; Dendritic Cells; Disease; Disease Outcome; Effectiveness; Experimental Autoimmune Encephalomyelitis; Formulation; Gel; Gelatin; Glucose; Goals; Health; 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; neuron loss; neuroprotection; prophylactic; response

 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.

 描述（由申请人提供）：多发性硬化（MS）是一种自身免疫性疾病，其引起与炎症介导的对覆盖脑和脊髓神经元的髓鞘的损伤相关的神经功能缺损.现在认为轴突损伤发生在疾病过程的早期，在每个新的病变中，伴随着由累积轴突损失引起的进行性和不可逆的残疾。中枢神经系统（CNS）的自身免疫性攻击被认为是MS的继发性致病因素。针对髓鞘抗原的自身免疫进一步加剧了神经变性的自催化过程。本文提出的方法旨在将MS治疗方法的两个必要组分联合收割机组合成解决树突细胞（DC）表型失衡和促进神经保护的单一策略。总体目标是阐明生物材料策略的生物材料和免疫学基础，该生物材料策略用于通过在聚乙二醇（PEG）水凝胶内的MS抗原特异性免疫抑制DC递送并结合神经保护因子神经调节蛋白-1（NRG-1）的递送来进行免疫调节，以改善MS的鼠实验性自身免疫性脑脊髓炎（EAE）模型。通过在体外免疫抑制分子治疗时与MS抗原接触而赋予抗原特异性和致耐受性，可以使用局部水凝胶系统，沿着神经保护剂NRG-1的释放，应用于颈淋巴结（cLN），以通过免疫调节和神经保护改善EAE疾病的结果。在这项研究中，一个简化的生物材料策略，与初步结果中所描述的证明的疗效，是基于在原位凝胶PEG水凝胶内的小鼠颈部位置的免疫抑制MS抗原特异性的小鼠DC的交付，最低限度地修改，目前的细胞粘附肽，RGD。提出了两个具体目的：1）证明组装的多功能生物材料的关键组分用于递送免疫抑制性、MS抗原特异性DC和NRG-1的功能性;和2）阐明多功能生物材料通过免疫调节和神经保护改善鼠EAE的功效，并鉴定关键构建体组分。