Polymer Constructs for Axon Regeneration in the Central Nervous System

用于中枢神经系统轴突再生的聚合物结构

• 批准号: 7615805
• 负责人: Rebecca Robinson
• 金额: $ 4.46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615805
• 关键词: Acute; Address; Adult; Adverse effects; Affect; Animals; Antibodies; Area; Astrocytes; Axon; Axotomy; Biological Assay; Biological Neural Networks; Cell Differentiation process; Cell Transplantation; Cell Transplants; Cells; Chondroitin Sulfate Proteoglycan; Cicatrix; Combined Modality Therapy; Crush Injury; Degenerative Disorder; Diarrhea; Dose; Drug Delivery Systems; Effectiveness; Emulsions; Encapsulated; Engineering; Environment; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Event; Exanthema; Eye; Fatty acid glycerol esters; Fiber; Fluorescence Microscopy; Future; Glaucoma; Glycolates; Goals; Gray unit of radiation dose; Green Fluorescent Proteins; Growth Associated Protein 43; Hydrogels; Immunoblotting; Implant; In Vitro; Injection of therapeutic agent; Injury; Microspheres; Modeling; Modification; Natural regeneration; Nerve; Nerve Crush; Nerve Regeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Ocular orbit; Optic Nerve; Optic Nerve Injuries; Oral Administration; Phosphate Buffer; Polymers; Production; Protein Tyrosine Kinase; Rattus; Receptor Inhibition; Recovery of Function; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Saline; Series; Side; Signal Pathway; Site; Solutions; Spectrum Analysis; Spinal Cord; Spinal cord injury; Stem cell transplant; System; Target Populations; Techniques; Testing; Transplantation; Traumatic Brain Injury; axon regeneration; base; biomaterial compatibility; cell injury; clinical application; combinatorial; compliance behavior; controlled release; cytotoxicity; functional disability; in vitro testing; in vivo; inhibitor/antagonist; injured; macrophage; minimally invasive; monolayer; nerve stem cell; neuron loss; novel; optic nerve regeneration; receptor expression; repaired; superior colliculus Corpora quadrigemina; treatment effect; ultraviolet; white matter

DESCRIPTION (provided by applicant): The adult central nervous system (CNS) has a very limited intrinsic ability to regenerate after injury. Traumatic brain injuries or neurodegenerative diseases cause neuronal cell leads to long-lasting functional impairments. The profound effect observed from these injuries results from a series of events that occurs immediately following injury and persists for several weeks. These events take place not only at the intrinsic level via intracellular signaling pathways but at the extrinsic level as well. Recent evidence indicates that in order to promote significant regeneration in the damaged CNS, a combinatorial approach addressing both the intrinsic and extrinsic barriers to regeneration is necessary. Our goal is to understand how modification of the post-injury microenvironment will affect nerve regeneration. Specifically, our hypothesis is that transplantation of neural progenitor cells (NPCs) into the retina combined with administration of an epidermal growth factor receptor (EGFR) inhibitor via an engineered construct will enhance nerve regeneration in an optic nerve axotomy model. This hypothesis is based on two observations: (1) NPCs can differentiate into neurons and incorporate into existing neural networks, and (2) administration of EGFR inhibitors to damaged optic nerve and spinal cord result in regeneration of injured neurons. We will use an optic nerve crush injury model to determine the effectiveness of our treatment. At the site of injury, we will implant a polymer construct allowing controlled delivery of the EGFR inhibitor, followed by injection of NPCs into the vitreous of the eye. Our specific aims are to: (1) develop and characterize a drug delivery system for the controlled release of the EGFR inhibitor, (2) develop and characterize a construct for in vivo delivery of the inhibitor at the injury site, and (3) assess the effects of a combinatorial treatment approach on nerve regeneration in vivo in an optic nerve injury model. Combinatorial treatments provide a promising new option for therapy in CNS repair. We believe this approach in conjunction with cell transplantation therapy will provide important information regarding nerve regeneration in the mature >CNS. Accomplishing the specific aims outlined will provide an understanding of nerve regeneration and the glial scar microenvironment in vivo. Relevance: The central nervous system has very limited repair capabilities. This limitation is due to neuronal cell death and a post-injury cellular environment that is not favorable to regrowth of nerves. A combinatorial treatment of transplantation of neural progenitor cells and administration of an epidermal growth factor inhibitor can address both of these factors simultaneously, thus providing a new avenue for therapy.

描述（由申请人提供）：成人中枢神经系统（CNS）在损伤后具有非常有限的内在再生能力。外伤性脑损伤或神经退行性疾病引起神经细胞长期功能损伤。从这些损伤中观察到的深刻影响是由损伤后立即发生的一系列事件引起的，并持续数周。这些事件不仅通过细胞内信号通路在内在水平上发生，而且在外在水平上也发生。最近的证据表明，为了促进受损中枢神经系统的显著再生，有必要采用组合方法解决再生的内在和外在障碍。我们的目标是了解损伤后微环境的改变如何影响神经再生。具体来说，我们的假设是，将神经祖细胞（npc）移植到视网膜中，并通过工程构建物给予表皮生长因子受体（EGFR）抑制剂，将增强视神经轴切模型中的神经再生。这一假设基于两个观察结果：(1)npc可以分化成神经元并融入现有的神经网络；(2)将EGFR抑制剂用于受损的视神经和脊髓可导致受损神经元的再生。我们将使用视神经挤压损伤模型来确定我们治疗的有效性。在受伤部位，我们将植入一个聚合物结构，允许控制EGFR抑制剂的递送，然后将npc注射到眼睛的玻璃体中。我们的具体目标是：(1)开发和表征一种用于控制EGFR抑制剂释放的药物传递系统，(2)开发和表征一种用于在损伤部位体内递送抑制剂的结构，以及(3)在视神经损伤模型中评估组合治疗方法对体内神经再生的影响。联合治疗为中枢神经系统修复提供了一种新的治疗方法。我们相信这种方法结合细胞移植治疗将为成熟>中枢神经系统的神经再生提供重要信息。完成概述的具体目标将提供对神经再生和神经胶质瘢痕微环境在体内的理解。相关性：中枢神经系统的修复能力非常有限。这种限制是由于神经元细胞死亡和损伤后的细胞环境不利于神经的再生。神经祖细胞移植和表皮生长因子抑制剂联合治疗可以同时解决这两种因素，从而为治疗提供了新的途径。