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.

项目摘要 脊髓上调节的中断导致交感神经和无对抗的副交感神经活动减少， 导致高位脊髓损伤（SCI）后的心脏和血液动力学紊乱。我们最近报道说， 胚胎移植可恢复肾上腺素能对血流动力学的调节， 大鼠SCI模型中中缝核衍生的神经祖细胞/干细胞（RN-NPC）。此前， 运动，一种可行的治疗干预，提高神经元活动，轴突再生，和生产 脊髓损伤后神经营养因子因此，我们认为，在损伤的脊髓中移植神经元能的NPC， 脊髓将重建5-羟色胺调节，以改善心脏功能，并将RN-NPC移植物与 运动可促进SCI后心脏活动、血流动力学和自主神经反射障碍的恢复。在 目的1，我们将确定移植的多巴胺能NPC与脊髓回路的整合是否 恢复交感神经调节，改善SCI后心脏电传导。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系统的重建， 调节以恢复心脏活动、血液动力学和自主反射障碍。总体而言，该项目将 为SCI后的治疗策略提供了新的见解。