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/T001488/2
• 负责人: Cathy Slack
• 金额: $ 6.34万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT001488%2F2
• 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易感性大幅增加。这对老年人的生活质量以及我们社会的社会和经济成本产生了重大影响，特别是考虑到目前全球人类预期寿命的增加。因此，迫切需要新的方法来减轻老年人健康状况不佳的负担，这一领域的一项重要发现是，衰老期间的健康状况可以受到遗传和环境因素的调节。此外，类似的生物过程在进化上不同的物种中调节健康的衰老。因此，我们可以使用简单的实验室模型，如果蝇，果蝇，来有效地研究驱动人类衰老和与年龄有关的疾病的机制。这种创新的方法将确定新的药理学靶点，调节疾病的根本原因-衰老本身。我们最近发现，如果我们抑制一种特定的细胞表面受体，代谢型谷氨酸受体或mGluR的活性，我们可以改善果蝇的健康衰老。这些受体存在于所有动物中。它们与氨基酸L-谷氨酸结合以激活细胞信号事件的级联。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。然而，我们还不了解抑制mGluR活性改善健康衰老的机制。这些信息对于实现这种新的衰老调节剂的全部功能意义至关重要。在这个项目中，我们将使用果蝇作为一个简单的模型来定义mGluR信号传导如何影响与年龄相关的健康。我们将在特定组织和动物生命过程中的某些时间点关闭mGluR表达，以确定mGluR活性在衰老过程中何时何地影响健康。我们将通过改变蛋白质序列中的特定氨基酸，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更长的寿命。我们的初步数据表明，除了长寿之外，抑制mGluR功能还可以促进对各种胁迫的抗性。这些影响与重要的应激反应基因表达的变化有关。我们将扩大这些研究，以分析全球变化的基因表达后，mGluR抑制使用RNA测序。这将使我们能够识别对mGluR抑制做出响应以促进长寿的生理过程。最后，我们将使用已在临床上用于其他目的的mGluR活性的良好表征的药理学抑制剂，并将其喂给成年果蝇，以确定其对寿命的年龄依赖性影响，这是开发这些抑制剂用于未来治疗年龄相关疾病的关键步骤。总之，这些知识将使我们能够充分利用一种新的进化保守的长寿调节因子。这是确定新药物靶点的一个重要阶段，可用于治疗多种与年龄有关的疾病，针对其共同的根本原因-衰老的生物过程-以促进整个生命过程中的人类健康和福祉。