Hedgehog signalling in lifespan determination and neuroprotection in Drosophila (HHneuro).

全球预期寿命的增加引发了神经退行性疾病和与年龄有关的影响的急剧上升。在细胞水平上，衰老与各种缺陷有关，这些缺陷最终导致大脑中神经元和支持神经胶质细胞的丧失，导致神经元突触网络和认知功能的损害。因此，迫切需要进一步努力促进细胞活力并揭示调节预期寿命的关键因素。在这个项目中，我们将使用果蝇模型系统，因为它提供了一个独特的平台来解决这个问题，因为它相对较短的寿命，遗传适应性和与哺乳动物的同源性。该项目的总体目的是揭示果蝇刺猬（Hh）信号通路在成年大脑寿命决定和衰老调节中的作用。我们的初步研究结果表明，神经系统中的Hh信号对果蝇的寿命至关重要，神经胶质通路的重新激活足以恢复Hh表型的缺失。我们的研究表明，在成人大脑中，神经元-皮层胶质细胞的交流对于Hh信号通路的作用是重要的。我们认为神经元中Hh的表达和分泌激活了神经胶质细胞中的Hh信号级联，进而驱动靶基因的Ci/ gli依赖性表达，从而介导神经胶质细胞的完整性和整体神经保护。我们提出的项目旨在阐明Hh在成人神经系统和衰老过程中的作用。最初，我们将使用最新的方法来确定神经胶质特异性Hh靶基因的全部曲目。这种方法将使我们能够确定在衰老过程中介导神经元活力和寿命延长的因素。对Hh突变果蝇神经胶质特异性基因表达谱的分析将揭示有关衰老过程的新基础知识和信息，并确定Hh突变果蝇寿命缩短的分子和细胞缺陷。从这个意义上说，我们将特别关注hh依赖性伴侣网络，我们已经确定它参与了这个过程。此外，我们的转录组分析还将突出神经保护因子和遗传途径，这些因子和遗传途径可以代表新的治疗靶点，以维持健康的衰老和延迟年龄相关疾病的发作。除了Hh在衰老中的作用外，我们还建议评估Hh信号传导在帕金森病果蝇体内模型中提供神经保护的能力。据我们所知，对Hh通路对神经系统年龄依赖性稳态的影响的深入分析以前从未得到过解决，这将使我们对成人大脑的衰老过程有新的认识。

The increase in life expectancy worldwide has triggered a dramatic upsurge in neurodegenerative diseases and age-associated effects. On a cellular level, ageing has been associated with various defects, which culminates in a loss of neurons and supporting glial cells in the brain, leading to impairment of neuronal synaptic networks and cognitive function. Therefore, further efforts to promote cellular viability and to unravel the pivotal elements regulating life expectancy are urgently required. In this project, we will use the model system Drosophila melanogaster because it offers a unique platform to address this question due to its relatively short lifespan, genetic amenability and homology to mammals. The overall purpose of the project is to unveil the role of the Drosophila Hedgehog (Hh) signalling pathway in lifespan determination and regulation of aging in the adult brain. Our initial findings indicate that Hh signalling in the nervous system is crucial for longevity in flies and that reactivation of the pathway in glia is sufficient to revert loss-of-Hh phenotypes. Our studies suggest that neuron-cortex glia communication is important for the action of the Hh signalling pathway in the adult brain. We propose that expression and secretion of Hh in neurons activates the Hh signalling cascade in the glial cells, which in turn drives the Ci/Gli-dependent expression of target genes, that mediate integrity of glial cell as well as overall neuroprotection.The project we propose aims to clarify the role of Hh in the adult nervous system and during aging. Initially, we will use up-to-date methodologies to identify the full repertoire of glial specific Hh target genes. This approach will allow us to identify factors mediating neuronal viability and lifespan extension during the ageing process. The analysis of glial specific gene-expression profiles in Hh mutant flies will reveal new basic knowledge and information about the aging process and identify the molecular and cellular defects underlying the shortened longevity of Hh mutant flies. In this sense, we will pay special attention to the Hh-dependent chaperone network, which we have already identified as being involved in this process. In addition, our transcriptome analysis will also highlight neuroprotective factors and genetic pathways that can represent new therapeutic targets to maintain healthy ageing and to delay the onset of age-associated diseases. Besides the role of Hh in aging, we also propose to evaluate the ability of Hh signalling to provide neuroprotection in Drosophila in vivo models for Parkinson´s Disease. To our knowledge, an in-depth analysis of the impact of the Hh pathway on age-dependent homeostasis of the nervous system has never been addressed before and will allow us to gain new insight in the aging process of the adult brain.