Integrating metabolic signals through FOXO transcriptional complexes.

通过 FOXO 转录复合物整合代谢信号。

• 批准号: BB/X000265/1
• 负责人: Cathy Slack
• 金额: $ 74.85万
• 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: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000265%2F1
• 关键词: Integrating; metabolic; signals; through; FOXO

The FOXO transcription factors are a group of proteins that play a key role in balancing energy intake versus energy usage. Maintaining such metabolic balance has important health consequences particularly as we age. For example, being overweight or obese increases our susceptibility to multiple long-term diseases during ageing and can have a substantial impact on quality of life. Given the current global rise in obesity levels, this poses serious social and economic concerns to society. New ways to reduce the burden of ill health associated with poor metabolic outcomes are therefore urgently required.An important finding in the field is that very similar biological processes regulate the way in which animals across evolutionarily diverse species maintain metabolic balance in response to changes in the nutritional environment. We can therefore use simple laboratory models such as the fruit-fly, Drosophila melanogaster, to effectively study the processes that drive human metabolic disease. This approach has already been used to identify new drug targets to treat diseases associated with disruptions to metabolic regulation including some forms of cancer. The FOXO proteins function downstream of the highly conserved insulin/IGF-like signalling (IIS) pathway. This pathway functions in different animals, including humans, to coordinate and allocate nutrients taken in from the environment to different tissues and physiological processes. Preventing proper functioning of this pathway causes similar disruptions to metabolic physiology in Drosophila and humans. FOXO proteins perform their role by directly binding to target genes within the DNA of the cell to change their expression. Interestingly, our recent data shows that the expression of a group of these genes that code for proteins with important functions in regulating metabolism are influenced by FOXO activity even when FOXO is unable to bind to DNA. This suggests that FOXO is regulating the expression of these genes not by directly binding to the DNA itself but by binding to other proteins that are localised to the DNA. Our data suggests that these FOXO-protein interactions are important for relaying metabolic information within the cell. We do not yet fully understand the nature of these FOXO-protein interactions, but this knowledge is essential to understand the different roles of FOXO proteins in metabolic regulation. In this project, we will use Drosophila as a simple model to define how FOXO proteins relay key metabolic signals and maintain metabolic health without binding to DNA. We will identify and characterise all the proteins that bind to and localise FOXO to target genes. We already have candidate proteins to test and so we will examine in more detail the nature of these interactions using both biochemical and protein interaction assays in living cells. We will also manipulate the expression and activity of our candidate proteins within specific tissues to determine the downstream processes for which these interactions are important in maintaining metabolic health. Together, this knowledge will enable us to fully characterise the role of these clinically relevant transcriptional regulators in coordinating appropriate metabolic responses. Abberrant FOXO activity is linked to metabolic disease but treatments targeting FOXO directly are difficult to implement because it has many different functions. This project is an essential stage for the identification of new drug targets that could be used to treat many diseases that are pathologically linked to poor metabolic health thereby promoting human health and well-being across the lifecourse.

FOXO转录因子是一组蛋白质，在平衡能量摄入与能量使用方面起着关键作用。保持这种新陈代谢平衡具有重要的健康后果，尤其是随着年龄的增长。例如，超重或肥胖会增加我们对衰老期间多种长期疾病的敏感性，并可能对生活质量产生重大影响。鉴于当前肥胖水平的全球增长，这对社会引起了严重的社会和经济关注。因此，迫切需要减轻与代谢不良结局相关的不良健康负担的新方法。该领域的一个重要发现是，非常相似的生物学过程调节了进化多样的物种跨营养环境变化的代谢平衡的方式。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代谢疾病的过程。这种方法已被用来识别新药物靶标，以治疗与包括某些形式的癌症有关的代谢调节中断相关的疾病。高度保守的胰岛素/IGF样信号传导（IIS）途径的FOXO蛋白在下游的下游功能。该途径在包括人类在内的不同动物中起作用，以协调和分配从环境中吸收的营养和不同的组织和生理过程。防止这种途径的正确功能会导致果蝇和人类代谢生理的类似破坏。 FOXO蛋白通过直接与细胞DNA内的靶基因结合以改变其表达来发挥作用。有趣的是，我们最近的数据表明，这些基因的表达在调节代谢中具有重要功能的蛋白质的代码也受到Foxo活性的影响，即使FoxO无法与DNA结合。这表明FOXO不是通过直接与DNA本身而是通过与其他与DNA的蛋白质结合来调节这些基因的表达。我们的数据表明，这些FOXO蛋白质相互作用对于将细胞内的代谢信息传递至关重要。我们尚未完全理解这些FOXO蛋白质相互作用的性质，但是这种知识对于了解Foxo蛋白在代谢调节中的不同作用至关重要。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FOXO蛋白如何中继钥匙代谢信号并保持代谢健康而不与DNA结合。我们将识别并表征与靶基因结合并将FOXO定位的所有蛋白质。我们已经有候选蛋白要测试，因此我们将使用生物化学细胞中的生化和蛋白质相互作用测定法更详细地检查这些相互作用的性质。我们还将操纵候选蛋白在特定组织中的表达和活性，以确定这些相互作用对于维持代谢健康很重要的下游过程。这些知识共同使我们能够充分表征这些临床相关的转录调节剂在协调适当的代谢反应中的作用。 Abberrant Foxo活动与代谢疾病有关，但针对Foxo的治疗方法很难实施，因为它具有许多不同的功能。该项目是确定新药物靶标的必不可少的阶段，可用于治疗许多在病理上与不良的代谢健康有关的疾病，从而促进整个生命的人类健康和福祉。