In vivo reprogramming of NG2 glia for neurogenesis

NG2 神经胶质细胞体内重编程促进神经发生

• 批准号: 10475224
• 负责人: Chun-Li Zhang
• 金额: $ 42.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475224
• 关键词: Adult; Animal Model; Animals; Astrocytes; Behavioral; Biological Process; Brain; CSPG4 gene; Caregivers; Cell Nucleus; Cell Transplantation; Cell physiology; Cells; Chemicals; Cicatrix; Clinical; Data; Emotional; Genetic; Goals; Human; Immune; In Vitro; Injury; Lead; Lentivirus; Lesion; Molecular; Mus; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; Pathologic; Patients; Play; Population; Process; Proliferating; Rabies virus; Recombinants; Recovery of Function; Research; Role; Site; Small Nuclear RNA; Spinal; Spinal Cord; Spinal cord injury; Synapses; Therapeutic; Tissue Preservation; Transplantation; Undifferentiated; Vesicular stomatitis Indiana virus; Work; axon growth; axon regeneration; base; cell type; clinical translation; clinically relevant; in vivo; inhibitor; injury recovery; innovation; mouse model; nerve injury; nerve stem cell; neural circuit; neural repair; neuroblast; neurogenesis; neuroinflammation; neuron loss; neuronal excitability; neuronal survival; patch clamp; postsynaptic; presynaptic; promoter; regenerative approach; repaired; response to injury; stem cells; transcriptome sequencing; tumorigenesis

Neuron loss is a frequent result of neural injury or degeneration. A fundamental but unresolved challenge is how to restore the lost neurons and repair the neural circuits in the adult central nervous system. Stem cell-based transplantation has limitations on immune compatibility, neuronal survival, and functional integration; and it has the potential for tumorigenesis. The long-term goal of this proposal is to define innovative regenerative strategies by using a patient’s own scar-forming cells without cell transplantation. In response to injury or neural degeneration, glial cells become reactive, proliferate, and form scars. Scar formation is initially beneficial by restricting damage but ultimately detrimental to neural regeneration through acting as a physical and chemical barrier to axonal regeneration and growth. Our prior research showed that reactive astrocytes can be in vivo reprogrammed to expandable neural progenitors, which can further produce mature neurons in the adult central nervous system. The current proposal will focus on NG2 glia, another major component of the glial scar. Our preliminary data indicate that they can be in vivo reprogrammed to become neurogenic. We here propose to determine the molecular and cellular mechanisms underlying the reprogramming process of NG2 glia in adult mouse. We will also examine the excitability and synaptic integrations of the induced neurons from NG2 glia. Finally, we will investigate the biological function of these newly generated neurons in a mouse model of neural injury. Results from this work may lead to paradigm-shifting regeneration-based therapeutic strategies for neural injury and degeneration.

神经元损失是神经损伤或变性的常见结果。一个根本但尚未解决的挑战是， 恢复成年人中枢神经系统中丢失的神经元和修复神经回路。基于干细胞的 移植在免疫相容性、神经元存活和功能整合方面具有局限性; 肿瘤发生的可能性。这项提案的长期目标是确定创新的再生战略 通过使用患者自身的疤痕形成细胞而不进行细胞移植。对损伤或神经系统的反应 在变性时，神经胶质细胞变得反应性、增殖并形成瘢痕。疤痕形成最初是有益的， 限制损伤，但最终不利于神经再生，通过充当物理和化学 轴突再生和生长的障碍。我们先前的研究表明，反应性星形胶质细胞可以在体内 重新编程为可扩展的神经祖细胞，其可以进一步在成年中枢神经系统中产生成熟的神经元。 神经系统目前的建议将集中在NG 2神经胶质，神经胶质瘢痕的另一个主要组成部分。我们 初步数据表明，它们可以在体内重编程成为神经原性的。我们在此提议， 确定成年NG 2胶质细胞重编程过程的分子和细胞机制 老鼠.我们还将研究NG 2胶质细胞诱导神经元的兴奋性和突触整合。 最后，我们将研究这些新产生的神经元在小鼠神经元模型中的生物学功能。 损伤这项工作的结果可能会导致范式转移的神经再生为基础的治疗策略， 损伤和退化。