Molecular Determinants for In vivo Functional Reprogramming of Cortical Output Neurons and Circuits

皮质输出神经元和电路体内功能重编程的分子决定因素

• 批准号: 10503138
• 负责人: Maria J Galazo
• 金额: $ 37.22万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503138
• 关键词: Amyotrophic Lateral Sclerosis; Axon; Behavior; Brain; Brain Injuries; Brain Stem; Cell Differentiation process; Cells; Cerebral cortex; Data; Degenerative Disorder; Embryo; Evaluation; Frontotemporal Dementia; Genetic Transcription; Goals; Health; Human; Impaired cognition; Injury; Life; Maintenance; Membrane; Molecular; Motor; Movement; Mus; Mutation; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Output; Population; Property; Signal Pathway; Signal Transduction; Source; Spinal Cord; Spinal cord damage; Spinal cord injury; Testing; Thalamic structure; Time; Trauma; Work; axon injury; base; brain circuitry; brain repair; clinically relevant; experimental study; in vitro testing; in vivo; neural circuit; neuron loss; repaired; response; restoration; success; transcriptome; Amyotrophic Lateral Sclerosis; Axon; Behavior; Brain; Brain Injuries; Brain Stem; Cell Differentiation process; Cells; Cerebral cortex; Data; Degenerative Disorder; Embryo; Evaluation; Frontotemporal Dementia; Genetic Transcription; Goals; Health; Human; Impaired cognition; Injury; Life; Maintenance; Membrane; Molecular; Motor; Movement; Mus; Mutation; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Output; Population; Property; Signal Pathway; Signal Transduction; Source; Spinal Cord; Spinal cord damage; Spinal cord injury; Testing; Thalamic structure; Time; Trauma; Work; axon injury; base; brain circuitry; brain repair; clinically relevant; experimental study; in vitro testing; in vivo; neural circuit; neuron loss; repaired; response; restoration; success; transcriptome

PROJECT SUMMARY/ABSTRACT Currently there is no successful treatment that restores damaged brain circuitry. Neuron loss by either neurodegenerative diseases or trauma causes neurological and cognitive dysfunction, posing a great burden for human health. There is a critical need to find strategies for neural circuit repair. Direct reprogramming approaches hold great promise for brain repair. Their success in functional circuit restoration will depend on their capacity to convert other cells into neurons with functions matching those of the neurons damaged in a circuit. This precise conversion has been observed in the mouse cerebral cortex between cortical output (corticofugal) neurons, which can acquire the connectivity properties, including long-range projections, typical of other corticofugal subtypes. Though this is a promising step forward toward circuit repair, this precise conversion has been observed when reprogramming is induced at embryonic or immature states. The mechanisms that preclude reprogramming in differentiated neurons or the mechanisms that keep neuron identity unchanged throughout life are not understood. Hence, our goal is to investigate mechanisms critical for maintaining neuron subtype identity in differentiated neurons and determine how they limit reprogramming over time. This will reveal barriers that preclude functional conversion between neuron subtypes in vivo. We propose to investigate these mechanisms in corticofugal neurons, specifically in the context of in vivo reprogramming of Corticothalamic neurons (CTn) to produce Subcerebral projection neurons (SCn), a clinically relevant neuron subtype that degenerates in Amyotrophic lateral sclerosis and whose axons are damaged by spinal cord injury. In this proposal we will investigate whether identity maintenance mechanisms can be manipulated for in vivo reprogramming of CTn into functional SCn (Aim 1), we will determine whether these mechanisms can be inactivated in mature CTn to eliminate barriers that preclude CTn conversion into SCn (Aim 2), and we will elucidate the underlying downstream signals that preclude conversion of CTn into SCn in vivo (Aim 3).

项目摘要/摘要 目前尚无成功的治疗方法可以恢复受损的脑电路。神经元丧失 神经退行性疾病或创伤会引起神经和认知功能障碍，为 人类健康。寻找神经回路修复的策略迫切需要。直接重新编程 方法对脑修复有很大的希望。他们在功能电路恢复中的成功将取决于他们 将其他细胞转换为具有与电路中受损的神经元相匹配的功能的神经元的能力。 在皮质输出之间（皮质法）之间的小鼠大脑皮层中观察到了这种精确的转化率 神经元可以获取连接性能，包括远程预测，典型的其他 皮质软体亚型。尽管这是向电路维修迈出的有希望的一步，但这种确切的转换具有 当在胚胎或不成熟状态下诱导重编程时观察到。 排除分化神经元或保持神经元的机制的机制 一生不变的身份不变。因此，我们的目标是调查至关重要的机制 维持分化神经元中的神经元亚型身份，并确定它们如何限制重新编程 时间。这将揭示障碍，即在体内排除神经元亚型之间的功能转化。我们建议 研究皮质法甘酸神经元中的这些机制，特别是在体内重编程的背景下 皮质丘脑神经元（CTN）产生脑脑投射神经元（SCN），这是一种临床相关的神经元 亚型在肌萎缩性侧性硬化症中退化，其轴突因脊髓损伤而受损。 在此提案中，我们将调查是否可以为体内操纵身份维持机制 将CTN重新编程为功能性SCN（AIM 1），我们将确定这些机制是否可以是 在成熟的CTN中灭活以消除排除CTN转换为SCN的障碍（AIM 2），我们将 阐明了在体内排除CTN转换为SCN的下游信号（AIM 3）。