Polymer Constructs for Axon Regeneration in the Central Nervous System

描述(申请人提供)：成人中枢神经系统(CNS)在受伤后再生的内在能力非常有限。创伤性脑损伤或神经退行性疾病会导致神经细胞，导致长期的功能损害。从这些损伤中观察到的深刻影响是在受伤后立即发生的一系列事件的结果，并持续了几个星期。这些事件不仅通过细胞内信号通路在内在水平上发生，也在外在水平上发生。最近的证据表明，为了促进受损中枢神经系统的显著再生，需要一种组合的方法来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。具体地说，我们的假设是，将神经前体细胞(NPC)移植到视网膜中，结合使用表皮生长因子受体(EGFR)抑制剂，通过工程构建将促进视神经切断模型中的神经再生。这一假说基于两个观察：(1)神经前体细胞可以分化为神经元，并整合到现有的神经网络中；(2)对受损的视神经和脊髓给予EGFR抑制剂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的治疗效果。在损伤部位，我们将植入一种聚合物结构，允许控制EGFR抑制剂的释放，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EGFR抑制剂的控释给药系统，(2)开发和表征损伤部位的体内给药结构，以及(3)在视神经损伤模型中评估联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治疗提供了一个很有前途的新选择。我们相信，这种方法结合细胞移植治疗将为成熟的中枢神经系统的神经再生提供重要的信息。完成概述的特定目标将有助于了解神经再生和体内胶质瘢痕微环境。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细胞死亡和损伤后不利于神经再生的细胞环境造成的。神经前体细胞移植和表皮生长因子抑制剂的联合治疗可以同时解决这两个因素，从而为治疗提供了一条新的途径。

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.