Combining Serotonergic Neural Progenitor Transplantation and Exercise to Improve Cardiac Disorders and Autonomic Dysreflexia After Spinal Cord Injury

结合血清素能神经祖细胞移植和运动来改善脊髓损伤后的心脏病和自主神经反射异常

• 批准号: 10571933
• 负责人: Shaoping Hou
• 金额: $ 36.9万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571933
• 关键词: Adult; Animals; Arrhythmia; Autonomic Dysreflexia; Axon; Blood Pressure; Brain Stem; Cardiac; Cardiovascular system; Cells; Chronic; Clinical; Control Groups; Coronary heart disease; Disease; Dobutamine; Embryo; Embryo Transfer; Exercise; FRAP1 gene; Female; Fostering; Functional disorder; Future; Genetic; Green Fluorescent Proteins; Growth; Heart; Heart Diseases; Heart failure; Hindlimb; Histologic; Human; Hypotension; Implant; Inbred F344 Rats; Incidence; Injury; Interneurons; Interruption; Intervention; Kidney; Lesion; Longitudinal Studies; Modeling; Myocardial dysfunction; Neurons; Nuclear Pore Complex; Orthostatic Hypotension; Pathway interactions; Production; Rat Transgene; Rattus; Recovery; Recovery of Function; Regulation; Reporting; Rest; Role; Serotonergic System; Serotonin; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Stem cell transplant; Synapses; Testing; Thallium Myocardial Perfusion Imaging Stress Test; Therapeutic; Therapeutic Intervention; Transplantation; Vertebral column; Western Blotting; axon regeneration; colorectal distension; combinatorial; comorbidity; effective therapy; heart function; heart rate variability; hemodynamics; improved; induced pluripotent stem cell; insight; mortality risk; nerve stem cell; neurotrophic factor; novel; pharmacologic; progenitor; raphe nuclei; receptor; reconstitution; reconstruction; recruit; serotonergic regulation; stem cells; translational potential

Project summary Disruption of supraspinal regulation causes reduced sympathetic and unopposed parasympathetic activity, leading to cardiac and hemodynamic disorders after high-level spinal cord injury (SCI). We recently reported that renewal of serotonergic regulation over hemodynamics could be achieved with transplantation of embryonic raphe nucleus-derived neural progenitors/stem cells (RN-NPCs) in a rat SCI model. It was previously showed that exercise, a viable therapeutic intervention, heightens neuronal activity, axonal regrowth, and production of neurotrophic factors after SCI. Accordingly, we posit that transplanting serotonergic NPCs in the injured spinal cord will reestablish serotonin regulation to improve cardiac function, and combining RN-NPC grafts with exercise will enhance the recovery of cardiac activity, hemodynamics, and autonomic dysreflexia after SCI. In Aim 1, we will determine whether integration of transplanted serotonergic NPCs with spinal cord circuitry will restore sympathetic regulation to improve cardiac electrical conduction following SCI. In Aim 2, we will test whether combining RN-NPC transplants with exercise will further enhance the reconstitution of sympathetic modulation to restore cardiac activity, hemodynamics, and autonomic dysreflexia. Overall, this project will provide novel insight into therapeutic strategy following SCI.

项目概要 脊髓上调节的破坏导致交感神经和不受对抗的副交感神经活动减少， 导致高水平脊髓损伤（SCI）后心脏和血流动力学紊乱。我们最近报道说 通过胚胎移植可以实现对血流动力学的血清素调节的更新 大鼠 SCI 模型中的中缝核源性神经祖细胞/干细胞 (RN-NPC)。之前已经展示过 这项运动是一种可行的治疗干预措施，可以增强神经元活动、轴突再生和产生 SCI 后的神经营养因子。因此，我们假设将血清素能 NPC 移植到受伤的脊髓中 脐带将重建血清素调节以改善心脏功能，并将 RN-NPC 移植物与 运动将增强 SCI 后心脏活动、血流动力学和自主神经反射异常的恢复。在 目标 1，我们将确定移植的血清素能 NPC 与脊髓回路的整合是否会 恢复交感神经调节以改善 SCI 后的心脏电传导。在目标 2 中，我们将测试 RN-NPC移植与运动相结合是否会进一步增强交感神经的重建 调节以恢复心脏活动、血流动力学和自主神经反射障碍。总体而言，该项目将 为 SCI 后的治疗策略提供新的见解。