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

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).

项目概要/摘要 目前还没有成功的治疗方法可以恢复受损的大脑回路。神经元损失 神经退行性疾病或创伤导致神经和认知功能障碍，给患者带来巨大负担 人类健康。迫切需要找到神经回路修复的策略。直接重编程 方法对大脑修复有很大希望。他们在功能性电路恢复方面的成功将取决于他们的 将其他细胞转化为神经元的能力，其功能与电路中受损的神经元的功能相匹配。 在小鼠大脑皮层中观察到皮质输出（皮质输出）之间的这种精确转换 神经元，它可以获得连接特性，包括远程投影，这是其他神经元的典型特征 离皮质亚型。尽管这是朝着电路修复迈出的充满希望的一步，但这种精确的转换已经 在胚胎或未成熟状态下诱导重编程时观察到。 阻止分化神经元重编程的机制或保持神经元的机制 一生不变的身份不被理解。因此，我们的目标是研究对于 维持分化神经元中的神经元亚型同一性，并确定它们如何限制重编程 时间。这将揭示阻碍体内神经元亚型之间功能转换的障碍。我们建议 研究皮质神经元的这些机制，特别是在体内重编程的背景下 皮质丘脑神经元 (CTn) 产生大脑下投射神经元 (SCn)，这是一种临床相关神经元 肌萎缩侧索硬化症中退化的亚型，其轴突因脊髓损伤而受损。 在本提案中，我们将研究是否可以在体内操纵身份维持机制 将 CTn 重新编程为功能性 SCn（目标 1），我们将确定这些机制是否可以 在成熟的 CTn 中失活，以消除阻止 CTn 转化为 SCn 的障碍（目标 2），我们将 阐明阻止 CTn 在体内转化为 SCn 的潜在下游信号（目标 3）。