Novel Regenerative Treatment of TBI and Post TBI Depression

随着士兵们从世界各地的战争中归来，创伤性脑损伤(TBI)已有报道 在退伍军人中。不同程度的脑结构损伤和功能/行为缺陷 由于创伤后应激障碍(PTSD)包括创伤后抑郁(PTD)是常见的 在这些患者中。到目前为止，对于急性或慢性颅脑损伤，基本上还没有有效的治疗方法。 病人。近年来，基于细胞的治疗提供了一种有吸引力的和连贯的方法 再生医学。根据最新进展和我们的初步数据，我们提出了一个 直接转化聚集在损伤周围的内源性星形胶质细胞的新延迟治疗 脑损伤后慢性期的“诱导神经元(INS)”。在轻度/中度脑外伤小鼠模型中， 针对反应性星形胶质细胞的直接重编程基因NeuroD1(ND1)将在 慢病毒注射治疗挫伤周围区域。我们假设血统内的人直接 重新编程通过利用现有的神经元，提供了一个可行的内源性新神经元来源 促进脑损伤后星形胶质细胞的增殖，有助于防止PTD的发展(特异性目标1)。我们 建议重新编程基因表达将有效地减少胶质增生或胶质瘢痕的形成 在颅脑损伤后的慢性期，这将减少再生的物理和化学障碍 并显著促进轴突生长和其他再生活动(目标2)。它更远了 跑台运动联合康复将改善ND1诱导基因的假说 调节、脑损伤后组织修复和功能活动(目标3)。我们建议，在这一组合中 治疗，宿主组织中出现的INS由BDNF和催产素等上调基因丰富 有利于与现有神经网络的集成。我们的初步数据表明 将星形胶质细胞转化为成熟神经元的可行性，增加再生/行为基因，以及 颅脑损伤后慢性心理行为改善。这次调查的目的是 展示并开发一种有效的治疗脑外伤相关PTD的退伍军人患者。

As soldiers are returning from wars around the globe, traumatic brain injury (TBI) has been reported among veterans. Brain structural damage of different degrees and functional/behavioral deficits such as post-traumatic stress disorder (PTSD) including post-TBI depression (PTD) are frequently seen among these patients. So far, there is basically no effective treatment for acute TBI or chronic patients. In recent years, cell-based therapy provides an attractive and coherent approach in regenerative medicine. Based on the latest advancement and our preliminary data, we propose a novel delayed treatment by directly converting endogenous astrocytes accumulated around the injury site into "induced neurons (iNs)" in the chronic phase after TBI. In a mild/moderate TBI mouse model, the direct reprogramming gene NeuroD1 (ND1) that targets reactive astrocytes will be expressed in the peri-contusion region by lentiviral injection. We hypothesize that the intra-lineage direct reprogramming provides a viable endogenous source of new neurons by leveraging existing proliferative astrocytes after TBI and helps to prevent the development of PTD (Specific Aim 1). We propose that the reprogramming gene expression will effectively reduce gliosis or glial scar formation during the chronic phase after TBI, which will lessen physical and chemical barriers for regeneration and significantly facilitate axonal outgrowth and other regenerative activities (Aim 2). It is further hypothesized that combined rehabilitation of treadmill exercise will improve ND1-induced gene regulation, post-TBI tissue repair and functional activities (Aim 3). We propose that, in the combination therapy, iNs arisen within the host tissue enriched by up-regulated genes such as BDNF and oxytocin are conducive to integration with existing neural networks. Our preliminary data demonstrate the feasibility of converting astrocytes into mature neurons, increased regenerative/behavioral genes, and improved psychological behaviors chronically after TBI. The goal of this investigation is to demonstrate and develop an effective treatment for veteran patients with TBI-related PTD.