Mechanisms Driving Regenerative Neurogenesis in Planarians

涡虫再生神经发生的驱动机制

基本信息

批准号：
10641949
负责人：
Rachel Helen Roberts-Galbraith
金额：
$ 37.75万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
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/10641949
关键词：
Acetylcholine Adult Animals Anterior Automobile Driving Behavior Behavioral Assay Biological Assay Brain Cells Central Nervous System Cephalic Complex Cues Development Dopamine Dorsal Failure 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 Neurobiology Neurodegenerative Disorders Neuroglia Neurons Neuropeptides Neurotransmitters Organ Outcome Partner in relationship Pathway interactions Patients Pattern Peripheral Nervous System Pharyngeal structure Planarians Platyhelminths Pluripotent Stem Cells Positioning Attribute Predatory Behavior Recovery Regenerative research Regulation Research Rest Role Serotonin Signal Induction Signal Transduction Spinal Cord Spinal cord injury Stem cell transplant Stimulus Stroke Structure Testing Tissues Traumatic injury Work adult stem cell brain tissue cell injury cell type dopaminergic neuron feeding functional restoration gamma-Aminobutyric Acid improved in vivo injury and repair innovation ischemic injury model organism neural neural repair neurogenesis neuron regeneration novel therapeutic intervention post stroke reconstitution regeneration model regenerative regenerative therapy repaired response response to injury stem cell differentiation stem cell therapy tissue regeneration transcription factor wound

项目摘要

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.

项目摘要人类会再生大脑的组织，脊髓较差。无法再生缺失或受损的细胞阻碍神经退行性后的生存和恢复疾病，中风，创伤或缺血性损伤或发育错误。与人类不同，其他动物可以有效地修复中央内部的戏剧性伤害或损害神经系统。自由生活的淡水扁虫称为Planarians拥有非凡的再生能力，包括完美的再生和更换所有的大脑和神经索组织。组织丢失或损坏后，平面人会重塑现有组织并使用成年多能干细胞替代各种细胞类型，包括数十种类型的神经元。平面人以适当的比率创建神经元然后重新处理并将神经元重新连接到靶标以恢复功能。长期目标是发现使用强大神经再生的分子和细胞基础平面人。朝向这个目标，第一个具体目的是识别和表征对多能干细胞再生神经发生重要的因素，聚焦首先是关于多巴胺能神经元的再生。四个转录因子编码基因对多巴胺能神经元亚型的再生和维持很重要已经被发现了。以下特定目标将提供关键信息关于环境线索如何促进多能干细胞中的大脑再生体内。第二个具体目的是检验神经发生上调的假设在受伤后的平面人中，通过伤口引起的信号传导机制。第三具体目的是检验普兰氏神经发生由极性驱动的假设提示，以便在适当的位置创建正确类型的新神经元。这由于使用高度再生模型有机体探索再生神经发生，因为新分子和行为分析的发展（例如Dap-Seq，活猎物测定）。拟议的研究很重要，因为它将提供基础理解成功的神经再生，以应对伤害，长期确定可以利用的途径或分子机制的目标改善人类再生疗法。