Reprogramming reactive glial cells into functional new neurons after SCI

SCI 后将反应性神经胶质细胞重编程为功能性新神经元

• 批准号: 10469682
• 负责人: Wei Wu
• 金额: $ 52.21万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469682
• 关键词: Adopted; Adult; Anatomy; Astrocytes; Attenuated; Behavioral; Bilateral; Brain Injuries; Cell Therapy; Cells; Cervical; Chondroitin Sulfate Proteoglycan; Chronic Phase; Cicatrix; Clinical; Complement 5a; Corticospinal Tracts; Dissection; Dorsal; Exhibits; Failure; Forelimb; Gliosis; Hand functions; Human; Impairment; Injury; Liver; Mediating; Modeling; Morbidity - disease rate; Motor; Mus; Natural regeneration; Neuroglia; Neurons; Organ; Paralysed; Pathway interactions; Patients; Phenotype; Play; Productivity; Proliferating; Quality of life; Recovery; Recovery of Function; Regenerative capacity; Role; Sensory; Site; Skin; Somatic Cell; Spinal Cord; Spinal cord injury; Stem cell transplant; Structure of rubrospinal tract; Synapses; Synaptic Transmission; Techniques; Testing; Tissues; Transplantation; Virus; base; functional disability; functional improvement; improved; in vivo; innovation; mortality; nerve injury; nerve stem cell; neural circuit; neuron loss; novel strategies; optogenetics; postsynaptic; presynaptic; relating to nervous system; repaired; response; reticulospinal tract; stem cells

PROJECT SUMMARY Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Human patients who survive SCI frequently live with paralysis and extremely reduced quality of life and productivity. SCI often results in a permanent loss of neurons and the disruption of neural circuits that are critical for normal motor, sensory, and autonomic function. It is crucial to replenish the lost neurons and reconstruct the broken neural circuits for functional recovery. Unlike some other tissues or organs in the body, such as skin and liver, which can undergo self-repair through proliferation of endogenous stem or somatic cells, adult spinal cord exhibits minimal regenerative capacity. Cellular transplantation of stem cell-derived neural progenitors or differentiated neurons holds clinical potential 12-18. However, cell therapy is relatively inefficient due to the failure of these cells to survive or fully adopt a functional phenotype especially under the chronic phase of neural injury. In contrast to transplantation-based therapy, we propose to employ a novel strategy to reprogram endogenous reactive glial cells to mature neurons for functional recovery after SCI. Glial cells are abundant and ubiquitously distributed in the adult spinal cord. They become reactive, proliferate, and form glial scars in response to damage, and play critical roles in modulating tissue damage and repair after injury. Of note, scar formation and secretion of chondroitin sulfate proteoglycans (CSPG) by reactive glial cells (e.g. astrocytes) are inhibitory for functional improvement. Attenuating reactive gliosis or reducing CSPG activity improves posttraumatic regeneration, whereas increasing reactive gliosis worsens brain injuries. Here we hypothesize that reprogramming reactive glial cells to neurons at the injury site will reduce local glial scar formation and enhance establishment of new neural circuit resulting in functional recovery. Using a cervical C5 dorsal hemisection model (C5 DH) and forelimb functional recovery assessments in adult mice, we will test this hypothesis with three specific aims. In Aim 1, we will determine functional integration of glia-converted neurons after the C5 DH. In Aim 2, we will determine the anatomical integration of glia-converted neurons into local neural circuitry after the C5 DH. Lastly, in Aim 3, we will determine functional roles of descending supraspinal and/or propriospinal pathways over induced neurons in promoting forelimb functional recovery after the C5 DH. The proposed strategy is expected to provide alternative neuronal subtypes that may facilitate functional recovery after SCI.

PROJECT SUMMARY Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Human patients who survive SCI frequently live with paralysis and extremely reduced quality of life and productivity. SCI often results in a permanent loss of neurons and the disruption of neural circuits that are critical for normal motor, sensory, and autonomic function. It is crucial to replenish the lost neurons and reconstruct the broken neural circuits for functional recovery. Unlike some other tissues or organs in the body, such as skin and liver, which can undergo self-repair through proliferation of endogenous stem or somatic cells, adult spinal cord exhibits minimal regenerative capacity. Cellular transplantation of stem cell-derived neural progenitors or differentiated neurons holds clinical potential 12-18. However, cell therapy is relatively inefficient due to the failure of these cells to survive or fully adopt a functional phenotype especially under the chronic phase of neural injury. In contrast to transplantation-based therapy, we propose to employ a novel strategy to reprogram endogenous reactive glial cells to mature neurons for functional recovery after SCI. Glial cells are abundant and ubiquitously distributed in the adult spinal cord. They become reactive, proliferate, and form glial scars in response to damage, and play critical roles in modulating tissue damage and repair after injury. Of note, scar formation and secretion of chondroitin sulfate proteoglycans (CSPG) by reactive glial cells (e.g. astrocytes) are inhibitory for functional improvement. Attenuating reactive gliosis or reducing CSPG activity improves posttraumatic regeneration, whereas increasing reactive gliosis worsens brain injuries. Here we hypothesize that reprogramming reactive glial cells to neurons at the injury site will reduce local glial scar formation and enhance establishment of new neural circuit resulting in functional recovery. Using a cervical C5 dorsal hemisection model (C5 DH) and forelimb functional recovery assessments in adult mice, we will test this hypothesis with three specific aims. In Aim 1, we will determine functional integration of glia-converted neurons after the C5 DH. In Aim 2, we will determine the anatomical integration of glia-converted neurons into local neural circuitry after the C5 DH. Lastly, in Aim 3, we will determine functional roles of descending supraspinal and/or propriospinal pathways over induced neurons in promoting forelimb functional recovery after the C5 DH. The proposed strategy is expected to provide alternative neuronal subtypes that may facilitate functional recovery after SCI.