Tolls and neurotrophins in central nervous system regeneration and repair in Drosophila

果蝇中枢神经系统再生和修复中的Toll和神经营养素

• 批准号: BB/R00871X/1
• 负责人: Alicia Hidalgo
• 金额: $ 63.65万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR00871X%2F1
• 关键词: Tolls; neurotrophins; central; nervous; system

Cells in the central nervous system (CNS) have a natural ability to respond to change. Glial and neuronal number, axons, dendrites, circuits and synapses can be formed or eliminated during development and throughout life, such as with learning, exercise and experience. Normally, the balance between generative and destructive plasticity maintains structural integrity and appropriate behaviour. This balance fails with ageing, neurodegeneration and brain tumours. The CNS does not regenerate after damage, so injury to the brain or spinal cord, stroke and neurodegeneration (e.g. Alzheimer's disease) result in devastating permanent disability. Discovering and understanding genetic mechanisms underlying cell plasticity is key to promote regeneration and repair.Toll Like Receptors (TLRs) and neurotrophin (NT) ligands both promote generative and destructive cell change. TLRs underlie innate immunity. In the brain TLRs are in all cells, and alterations in TLRs underlie brain diseases, e.g. stroke, neurodegeneration, multiple sclerosis and anxiety. TLRs induce microglia activation and debris phagocytosis, cell survival and death, neurite growth and collapse. However their in vivo functions are poorly understood and their neuronal functions and endogenous CNS ligands, are both unknown. The NTs are the main neuroprotective factors, and NT problems underlie most brain diseases, from neurodegeneration to epilepsy and depression. NTs promote from neuronal survival and connectivity to synaptic transmission, in development, learning and with experience. NTs also have destructive functions. How NT functions are balanced in vivo, across cell types and circuits, is poorly understood.We discovered that Tolls are receptors for Drosophila neurotrophins (DNTs) in the fruit-fly, and that human NTs and TLRs can interact too. Drosophila is a very powerful model organism to identify gene networks and test gene function in vivo, and it is often used to investigate regeneration and repair. Genes discovered in fruit-flies are tested in mammals, expediting research findings for human health and minimizing animal use.We discovered a novel mechanism balancing cell survival and death during neural circuitry involving DNTs and Tolls. We also discovered a gene network underlying the glial regenerative response to injury that involves NFkB, the universal effector of Tolls and TLRs. Preliminary findings indicate that DNTs and Tolls could be involved in both glial and neuronal regeneration.Harnessing our recent findings, we aim to work out how glia and neurons elicit coordinated change, to promote regeneration and repair. We will test the hypothesis that distinct DNT/Toll/adaptor modules regulate the response of glial cells, neurons and neuron-glia interactions to injury. 22 genes and over 33 proteins are potentially involved. Our strategy will be to identify the modules most relevant for neurons or glia and test 2-5 in regeneration and repair. The objectives are: (1) to visualize a map of DNTs and Tolls in the ventral nerve cord (VNC), and select neuronal and glial pairs. (2) We anticipate some overlap and some specificity in DNT-Toll interactions, and differential affinities of Tolls for the adaptor Wek can shift their function from neuroprotective to pro-apoptotic. So to narrow down, we will test and select the most specific DNT-Toll, and Toll-Wek pairs. (3) Test whether the selected 2-5 DNT/Toll/adaptor modules regulate in vivo glial (cell debris phagocytosis, glial proliferation, axonal enwrapment) or neuronal (neuroprotection, neurogenesis, axonal/dendritic patterns and circuitry) responses to injury, and whether manipulating these genes promotes regeneration and repair.The outcome will be a gene network involving DNTs and Tolls for CNS regeneration and repair. Even if not all details were to be evolutionarily conserved, our framework will provide incisive predictions that can be tested in mammals, ultimately for the benefit of human health.

中枢神经系统 (CNS) 中的细胞具有对变化做出反应的天然能力。神经胶质和神经元数量、轴突、树突、回路和突触可以在发育过程中和整个生命过程中形成或消除，例如通过学习、锻炼和经验。通常，生成性和破坏性可塑性之间的平衡可以维持结构完整性和适当的行为。这种平衡会随着衰老、神经退行性疾病和脑肿瘤而失效。中枢神经系统受损后无法再生，因此大脑或脊髓损伤、中风和神经退行性疾病（例如阿尔茨海默病）会导致毁灭性的永久性残疾。发现和理解细胞可塑性背后的遗传机制是促进再生和修复的关键。Toll 样受体 (TLR) 和神经营养蛋白 (NT) 配体均促进生成性和破坏性细胞变化。 TLR 是先天免疫的基础。在大脑中，TLR 存在于所有细胞中，TLR 的改变是脑部疾病的基础，例如脑部疾病。中风、神经退行性疾病、多发性硬化症和焦虑。 TLR 诱导小胶质细胞激活和碎片吞噬、细胞存活和死亡、神经突生长和塌陷。然而，人们对它们的体内功能知之甚少，并且它们的神经元功能和内源性 CNS 配体都是未知的。 NT 是主要的神经保护因素，NT 问题是大多数脑部疾病的根源，从神经退行性疾病到癫痫和抑郁症。 NT 在发育、学习和经验中促进从神经元存活和连接到突触传递。 NT也具有破坏性功能。人们对 NT 功能如何在体内跨细胞类型和回路保持平衡知之甚少。我们发现 Tolls 是果蝇中果蝇神经营养素 (DNT) 的受体，人类 NT 和 TLR 也可以相互作用。果蝇是一种非常强大的模式生物，可以识别基因网络并测试体内基因功能，并且经常用于研究再生和修复。在果蝇中发现的基因在哺乳动物中进行了测试，从而加快了人类健康的研究结果并最大限度地减少了动物的使用。我们发现了一种在涉及 DNT 和 Tolls 的神经回路中平衡细胞生存和死亡的新机制。我们还发现了神经胶质细胞对损伤的再生反应的基因网络，该网络涉及 NFkB（Tolls 和 TLR 的通用效应器）。初步研究结果表明，DNT 和 Tolls 可能参与神经胶质和神经元的再生。利用我们最近的发现，我们的目标是弄清楚神经胶质和神经元如何引发协调变化，以促进再生和修复。我们将测试以下假设：不同的 DNT/Toll/适配器模块调节神经胶质细胞、神经元和神经元-神经胶质细胞相互作用对损伤的反应。可能涉及 22 个基因和超过 33 个蛋白质。我们的策略是确定与神经元或神经胶质细胞最相关的模块，并测试再生和修复中的 2-5 个模块。目标是：(1) 可视化腹神经索 (VNC) 中的 DNT 和 Tolls 地图，并选择神经元和神经胶质对。 (2) 我们预计 DNT-Toll 相互作用中存在一些重叠和一些特异性，并且 Tolls 对适配器 Wek 的不同亲和力可以将其功能从神经保护转变为促凋亡。因此，为了缩小范围，我们将测试并选择最具体的 DNT-Toll 和 Toll-Wek 对。 (3)测试所选的2-5个DNT/Toll/适配器模块是否调节体内神经胶质（细胞碎片吞噬、神经胶质增殖、轴突包裹）或神经元（神经保护、神经发生、轴突/树突模式和电路）对损伤的反应，以及操纵这些基因是否促进再生和修复。结果将是一个基因网络 涉及中枢神经系统再生和修复的 DNT 和 Tolls。即使并非所有细节都在进化上得到保留，我们的框架也将提供可以在哺乳动物中进行测试的精辟预测，最终造福人类健康。

项目成果

Regenerative neurogenic response from glia requires insulin-driven neuron-glia communication.

• DOI: 10.7554/elife.58756
• 发表时间: 2021-02-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Harrison NJ;Connolly E;Gascón Gubieda A;Yang Z;Altenhein B;Losada Perez M;Moreira M;Sun J;Hidalgo A
• 通讯作者: Hidalgo A

Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

神经胶质细胞的再生神经反应需要胰岛素驱动的神经元-神经胶质细胞通讯

• DOI: 10.1101/721498
• 发表时间: 2019
• 作者: Harrison N