Novel Regenerative Treatment of TBI and Post TBI Depression

TBI 和 TBI 后抑郁症的新型再生治疗

• 批准号: 10385693
• 负责人: Shan P. Yu
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385693
• 关键词: Accidents; Acute; Area; Astrocytes; Athletic Injuries; Attenuated; Autologous; Axon; Behavior; Behavioral; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Bypass; Cell Therapy; Cell Transplantation; Cells; Chemicals; Chronic; Chronic Phase; Cicatrix; Combined Modality Therapy; Contusions; Data; Development; Ectopic Expression; Exercise; Gene Expression; Gene Expression Regulation; Genes; Gliosis; Goals; Health; In Vitro; Injections; Injury; Investigation; Lentivirus Vector; Lesion; Mental Depression; Mental disorders; Mitotic; Modeling; Mus; Natural regeneration; Neuroglia; Neuronal Plasticity; Neurons; Neuroprotective Agents; Oxytocin; Patients; Pharmacotherapy; Physiological; Pluripotent Stem Cells; Post-Traumatic Stress Disorders; Recovery of Function; Regenerative Medicine; Rehabilitation therapy; Reporting; Research; Risk; Signal Transduction; Site; Soldier; Somatic Cell; Source; Spinal cord injury; Stem cell transplant; TBI Patients; TBI treatment; Testing; Therapeutic; Therapeutic Effect; Tissues; Transplantation; Traumatic Brain Injury; Up-Regulation; Veterans; War; adult neurogenesis; astrogliosis; axon growth; axon regeneration; base; behavior test; brain tissue; cell type; central nervous system injury; chronic depression; clinical translation; combat; controlled cortical impact; delivery vehicle; disability; effective therapy; experimental study; improved; in vivo; middle age; mouse model; nerve stem cell; neural network; neurogenesis; neurovascular injury; novel; novel therapeutics; prevent; protective effect; psychologic; reconstruction; regenerative; regenerative treatment; repaired; sex; stroke therapy; subventricular zone; success; synaptogenesis; tissue repair; transcription factor; treadmill; tumor

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.

随着士兵从世界各地的战争中返回，出现了创伤性脑损伤 (TBI) 的报告 退伍军人之中。不同程度的脑结构损伤和功能/行为缺陷，例如 创伤后应激障碍 (PTSD) 包括创伤后应激障碍 (PTD) 很常见 在这些患者中。迄今为止，对于急性TBI或慢性TBI基本上没有有效的治疗方法。 患者。近年来，基于细胞的治疗提供了一种有吸引力且连贯的方法 再生医学。根据最新进展和我们的初步数据，我们提出了 通过直接转化损伤周围聚集的内源性星形胶质细胞来进行新型延迟治疗 TBI 后慢性期中的位点进入“诱导神经元 (iNs)”。在轻度/中度 TBI 小鼠模型中， 靶向反应性星形胶质细胞的直接重编程基因 NeuroD1 (ND1) 将在 通过慢病毒注射到达挫伤周围区域。我们假设谱系内直接 重编程通过利用现有的神经元提供了可行的内源性新神经元来源 TBI 后星形胶质细胞的增殖，有助于预防 PTD 的发展（具体目标 1）。我们 提出重编程基因表达将有效减少神经胶质增生或神经胶质疤痕形成 在 TBI 后的慢性阶段，这将减少再生的物理和化学障碍 并显着促进轴突生长和其他再生活动（目标 2）。更是进一步 假设跑步机运动联合康复将改善 ND1 诱导基因 调节、TBI 后组织修复和功能活动（目标 3）。我们建议，在组合中 治疗期间，宿主组织内产生的 iNs 富含 BDNF 和催产素等上调基因 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 TBI 后长期改善心理行为。这项调查的目的是 展示并开发一种针对患有 TBI 相关 PTD 的退伍军人患者的有效治疗方法。