Metabotropic glutamate receptor signalling: a new drug target for longevity.

代谢型谷氨酸受体信号传导：长寿的新药物靶点。

• 批准号: BB/T001488/1
• 负责人: Cathy Slack
• 金额: $ 55.36万
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT001488%2F1
• 关键词: Metabotropic; glutamate; receptor; signalling; new

As we age, our susceptibility to multiple long-term diseases substantially increases. This has a significant impact on quality of life for older people as well as social and economic costs to our society, particularly given the current global rise in human life expectancy. Thus, new ways to reduce the burden of ill health in older people are urgently required.An important finding in the field is that health during ageing can be modulated by both genetic and environmental factors. Furthermore, similar biological processes regulate healthy ageing across evolutionarily diverse species. We can therefore use simple laboratory models such as the fruit-fly, Drosophila melanogaster, to effectively study the mechanisms that drive human ageing and age-related diseases. This innovative approach will identify new pharmacological targets that modulate the underlying cause of disease - ageing itself.We have recently discovered that we can improve healthy ageing in Drosophila if we inhibit the activity of a specific cell-surface receptor, the metabotropic glutamate receptor or mGluR. These receptors are present in all animals. They bind to the amino acid L-glutamate to activate a cascade of cell signalling events. The activity of these receptors has already been shown to have important implications for human health as highlighted by their involvement in several neurological disorders. However, we do not yet understand the mechanisms by which inhibition of mGluR activity improves healthy ageing. This information is essential to realise the full functional significance of this new ageing regulator.In this project, we will use Drosophila as a simple model to define how mGluR signalling impacts on age-related health. We will switch off mGluR expression in specific tissues and at certain time-points during the lifecourse of the animals to identify where and when mGluR activity influences health during ageing. We will disrupt receptor function in more precise ways by changing specific amino acids within the protein sequence. We will also alter the activity of various downstream signalling molecules to determine how disruption of mGluR function leads to longer lifespan. Our preliminary data shows that as well as longevity, inhibition of mGluR function also promotes resistance to various stresses. These effects are associated with changes in the expression of important stress responsive genes. We will expand these studies to analyse the global changes in gene expression upon mGluR inhibition using RNA-sequencing. This will allow us to identify the physiological processes that are responding to mGluR inhibition to promote longevity. Lastly, we will use well-characterised pharmacological inhibitors of mGluR activity that are already used in the clinic for other purposes and feed them to adult flies to determine their age-dependent effects on longevity, a critical step in the development of these inhibitors for future therapeutics for age-related disease. Together, this knowledge will enable us to fully characterise a new evolutionarily conserved longevity regulator. This is an essential stage for the identification of new drug targets that could be used to treat multiple age-related diseases by targeting their common underlying cause - the biological processes of ageing - to promote human health and well-being across the lifecourse.

随着年龄的增长，我们对多种长期疾病的敏感性大大增加。这对老年人的生活质量以及社会和经济成本对我们的社会产生了重大影响，尤其是考虑到人类预期寿命的全球增长。因此，迫切需要减轻老年人健康负担的新方法。该领域的一个重要发现是，在衰老过程中，遗传和环境因素可以调节衰老期间的健康。此外，类似的生物学过程调节整个进化上多种物种的健康衰老。因此，我们可以使用简单的实验室模型，例如水果果蝇果蝇（Drosophila Melanogaster），可以有效研究驱动人类衰老和与年龄相关的疾病的机制。这种创新的方法将确定调节疾病根本原因的新药理靶标 - 我们最近发现，如果我们抑制特定细胞表面受体的活性，代替谷氨酸受体或mglur，我们可以改善果蝇的健康衰老。这些受体都存在于所有动物中。它们与氨基酸L-谷氨酸结合以激活一系列细胞信号事件。这些受体的活性已经被证明对人类健康具有重要意义，因为它们参与了几种神经系统疾病。但是，我们尚不了解抑制MGLUR活性可以改善健康衰老的机制。这些信息对于实现这个新的老化调节器的全部功能意义至关重要。在该项目中，我们将使用果蝇作为一个简单的模型来定义mglur信号如何影响与年龄相关的健康。我们将关闭动物生命过程中特定组织和特定时间点的MGlur表达，以识别MGLUR活动在衰老期间影响健康的何时何地。通过改变蛋白质序列中的特定氨基酸，我们将以更精确的方式破坏受体功能。我们还将改变各种下游信号分子的活性，以确定mglur功能的破坏如何导致寿命更长。我们的初步数据表明，以及寿命和抑制MGLUR功能还促进了对各种应力的抵抗力。这些影响与重要胁迫反应基因的表达变化有关。我们将扩展这些研究，以分析使用RNA测序后MGLUR抑制后基因表达的全球变化。这将使我们能够确定对MGLUR抑制作用以促进寿命的生理过程。最后，我们将使用良好的MGLUR活性的药理学抑制剂，这些抑制剂已在诊所中用于其他目的，并将其喂入成人苍蝇，以确定其对寿命的依赖性影响，这是这些抑制剂开发未来治疗因素的关键步骤。这些知识将共同使我们能够充分表征一个新的进化保守的寿命调节器。这是确定新药物靶标的必不可少的阶段，可以通过靶向其共同的潜在原因（衰老的生物学过程）来促进整个生命的人类健康和福祉，以治疗多种年龄相关的疾病。