Neurogenesis in the adult Drosophila brain

成年果蝇大脑的神经发生

• 批准号: 10587326
• 负责人: GRACE E BOEKHOFF-FALK
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587326
• 关键词: Acceleration; Address; Adult; Affect; Apoptosis; Axon; Behavior; Behavioral; Behavioral Assay; Brain; Brain Injuries; Candidate Disease Gene; Cell Death; Cell Proliferation; Cells; Circadian Rhythms; Compensation; Cyclin-Dependent Kinase Inhibitor; Data; Dendrites; Development; Drosophila genus; Drosophila melanogaster; Gene Expression; Generations; Genes; Genetic; Genetic Models; Goals; Human; Immune; Immunohistochemistry; Injury; Innate Immune System; Knowledge; Label; Laboratories; Locomotor Recovery; Mediating; Medical; Modeling; Molecular; Natural Immunity; Natural regeneration; Nerve Regeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropil; Optic Lobe; Pathway interactions; Population; Proliferating; RNA Interference; Recovery of Function; Reporting; Role; Signal Pathway; Stem cell transplant; Testing; Therapeutic; Time; Work; adult neurogenesis; brain cell; candidate identification; clinical application; clinically relevant; experimental study; gliogenesis; injury recovery; innovation; knock-down; model organism; mutant; nerve stem cell; neural; neural circuit; neurogenesis; neuron regeneration; novel; progenitor; regenerative; response; therapeutic target; timeline

Project Summary One of the barriers to therapeutic neural regeneration in humans is the absence of neural stem cells in most regions of the adult brain. Nonetheless, it would be advantageous to induce regeneration from resident cells. In addition, progress in the field would be accelerated if neural regeneration from resident cells could be investigated using a genetic model organism. Toward this end, we have developed a novel adult neurogenesis model in the Drosophila melanogaster central brain. We find that despite the absence of known neural progenitors, cells in the adult Drosophila central brain proliferate following injury, giving rise to both new neurons and new glial cells. Further, the new neurons project both axons and dendrites to specific target regions. We also observe functional recovery of behavioral deficits, suggesting that the new neurons integrate appropriately into neural circuits. Our results are paradigm-shifting because they suggest that resident brain cells can mediate neural regeneration. Here, we propose to utilize the model to investigate the signaling pathways and cellular mechanisms that regulate adult neurogenesis. Based on compelling preliminary data, our central hypothesis is that adult-born neurons are responsible for functional recovery from brain injury and that these neurons arise separately from adult-born glia. This hypothesis is supported by multiple lines of evidence from our ongoing work. We have identified, and are now investigating, genes uniquely upregulated during neural regeneration. The work proposed here will provide critical data about the molecular mechanisms that underlie that adult neurogenesis. Our work is innovative and has translational relevance because it shifts the focus of neural regeneration away from stem cell transplants and toward resident cell populations and it may lead to the identification of therapeutic targets for the stimulation of brain regeneration in humans.

项目摘要 人类治疗性神经再生的障碍之一是大多数人缺乏神经干细胞。 成人大脑的区域。尽管如此，从驻留细胞诱导再生将是有利的。在 此外，如果能够从驻留细胞中再生神经， 使用遗传模式生物进行研究。为此，我们开发了一种新的成人神经发生 果蝇（Drosophila melanogaster）中央脑的模型。我们发现，尽管缺乏已知的神经 成年果蝇中枢脑中的祖细胞在损伤后增殖，产生新的 神经元和新的神经胶质细胞。此外，新的神经元将轴突和树突投射到特定的靶点， 地区我们还观察到行为缺陷的功能恢复，这表明新的神经元整合 适当地进入神经回路。我们的研究结果是一种范式转变，因为它们表明， 细胞可以介导神经再生。在这里，我们建议利用该模型来研究信号 调节成人神经发生的途径和细胞机制。根据令人信服的初步数据， 我们的中心假设是，成人出生的神经元负责脑损伤的功能恢复， 这些神经元是独立于成人神经胶质细胞产生的。这一假设得到了多条线的支持， 我们正在进行的工作的证据。我们已经确定，现在正在调查，基因独特的上调 在神经再生过程中。这里提出的工作将提供有关分子机制的关键数据 这是成年人神经发生基础。我们的工作是创新的，具有翻译相关性，因为它改变了 神经再生的焦点从干细胞移植转向常驻细胞群， 可能导致用于刺激人类脑再生的治疗靶点的鉴定。