Mechanisms Driving Regenerative Neurogenesis in Planarians

涡虫再生神经发生的驱动机制

• 批准号: 10503711
• 负责人: Rachel Helen Roberts-Galbraith
• 金额: $ 33.39万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503711
• 关键词: Acetylcholine; Adult; Animal Model; Animals; Anterior; Automobile Driving; Behavior; Behavioral Assay; Biological Assay; Brain; Cells; Cephalic; Complex; Cues; Development; Dopamine; Dorsal; Failure; Foundations; Fresh Water; Ganglia; Genes; Glutamates; Goals; Health; Homeostasis; Human; Injury; Laboratories; Location; Maintenance; Modeling; Molecular; Movement; Muscle; Natural regeneration; Nature; Nerve; Nerve Regeneration; Nerve Tissue; Nervous system structure; Neuraxis; Neurobiology; Neurodegenerative Disorders; Neurons; Neuropeptides; Neurotransmitters; Organ; Outcome; Partner in relationship; Pathway interactions; Patients; Pattern; Peripheral Nervous System; Pharyngeal structure; Planarians; Platyhelminths; Pluripotent Stem Cells; Positioning Attribute; Recovery; Regenerative research; Regulation; Research; Rest; Role; Serotonin; Signal Transduction; Spinal Cord; Spinal cord injury; Stem cell transplant; Stimulus; Stroke; Structure; Testing; Tissues; Traumatic injury; Work; brain tissue; cell injury; cell type; dopaminergic neuron; feeding; functional restoration; gamma-Aminobutyric Acid; improved; in vivo; injury and repair; innovation; ischemic injury; neural repair; neurogenesis; neuron regeneration; novel therapeutic intervention; post stroke; reconstitution; regeneration model; regenerative; regenerative therapy; relating to nervous system; repaired; response; response to injury; stem; stem cell differentiation; stem cell therapy; tissue regeneration; transcription factor; wound

Project Summary Humans regenerate tissue of the brain and spinal cord poorly. Failure to regenerate missing or damaged cells impedes survival and recovery after neurodegenerative disease, stroke, traumatic or ischemic injury, or developmental error. Unlike humans, other animals can effectively repair dramatic injuries or damage within the central nervous system. Free-living freshwater flatworms called planarians possess extraordinary regenerative abilities, including flawless regeneration and replacement of all brain and nerve cord tissues. After tissue loss or damage, planarians remodel existing tissue and use adult pluripotent stem cells to replace diverse cell types, including dozens of types of neurons. Planarians create neurons in appropriate ratios and then repattern and reconnect neurons to targets to restore function. The long-term goal is to discover the molecular and cellular basis of robust neural regeneration using planarians. Toward that objective, the first specific aim is to identify and characterize factors important for regenerative neurogenesis from pluripotent stem cells, focusing first on regeneration of dopaminergic neurons. Four transcription factor-encoding genes important for regeneration and maintenance of dopaminergic neuron subtypes have already been discovered. The following specific aims will provide critical information about how environmental cues promote brain regeneration by pluripotent stem cells in vivo. The second specific aim is to test the hypothesis that neurogenesis is upregulated in planarians after injury, through wound-induced signaling mechanisms. The third specific aim is to test the hypothesis that planarian neurogenesis is driven by polarity cues so that new neurons of the correct types are created in the proper locations. The proposed work in this application is conceptually innovative because of the use of a highly regenerative model organism to explore regenerative neurogenesis and because of the development of new molecular and behavioral assays (e.g. DAP-Seq, live prey assays). The proposed research is significant because it will provide a foundational understanding of successful neural regeneration in response to injury, with a long-term goal of identifying pathways or molecular mechanisms that could be leveraged to improve human regenerative therapies.

项目概要 人类大脑和脊髓组织的再生能力很差。无法再生 细胞缺失或受损会阻碍神经退行性疾病后的存活和恢复 疾病、中风、创伤性或缺血性损伤，或发育错误。与人类不同， 其他动物可以有效修复中枢神经系统的严重损伤或损伤 神经系统。自由生活的淡水扁虫（称为涡虫）拥有 非凡的再生能力，包括完美的再生和替换 所有脑和神经索组织。组织损失或损伤后，涡虫会重塑 现有组织并使用成体多能干细胞替代多种细胞类型， 包括数十种神经元。涡虫以适当的比例产生神经元 然后重新排列神经元并将其与目标重新连接以恢复功能。长期来看 目标是发现强大的神经再生的分子和细胞基础 涡虫。为了实现这一目标，第一个具体目标是确定和表征 对多能干细胞再生神经发生很重要的因素，重点关注 首先是多巴胺能神经元的再生。四种转录因子编码基因 对于多巴胺能神经元亚型的再生和维持很重要 已经被发现了。以下具体目标将提供关键信息 关于环境因素如何通过多能干细胞促进大脑再生 体内。第二个具体目标是检验神经发生上调的假设 在涡虫受伤后，通过伤口诱导的信号机制。第三个 具体目的是检验涡虫神经发生是由极性驱动的假设 提示，以便在正确的位置创建正确类型的新神经元。这 本申请中提出的工作在概念上具有创新性，因为使用了 高度再生的模型生物体探索再生神经发生，因为 新分子和行为分析（例如 DAP-Seq、活体猎物 化验）。拟议的研究意义重大，因为它将提供基础 了解针对损伤的成功神经再生，并具有长期的 确定可用于的途径或分子机制的目标 改善人类再生疗法。