Integrating metabolic signals through FOXO transcriptional complexes.

FOXO转录因子是一组在平衡能量摄入与能量使用方面发挥关键作用的蛋白质。保持这种代谢平衡对健康有重要的影响，特别是随着年龄的增长。例如，超重或肥胖会增加我们在衰老过程中对多种长期疾病的易感性，并对生活质量产生重大影响。鉴于目前全球肥胖水平上升，这给社会带来了严重的社会和经济问题。因此，迫切需要新的方法来减轻与不良代谢结果相关的健康状况不佳的负担。该领域的一个重要发现是，非常相似的生物过程调节进化上不同物种的动物维持代谢平衡的方式，以应对营养环境的变化。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代谢疾病的过程。这种方法已经被用于确定新的药物靶点，以治疗与代谢调节中断相关的疾病，包括某些形式的癌症。FOXO蛋白在高度保守的胰岛素/IGF样信号传导（IIS）通路下游发挥作用。这一途径在包括人类在内的不同动物中发挥作用，以协调和分配从环境中摄取的营养物质到不同的组织和生理过程。阻止这一途径的正常运作会对果蝇和人类的代谢生理造成类似的破坏。FOXO蛋白通过直接结合细胞DNA内的靶基因以改变其表达来发挥作用。有趣的是，我们最近的数据表明，即使FOXO不能与DNA结合，一组编码在调节代谢中具有重要功能的蛋白质的基因的表达也会受到FOXO活性的影响。这表明FOXO不是通过直接结合DNA本身，而是通过结合定位于DNA的其他蛋白质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传递细胞内的代谢信息很重要。我们还没有完全了解这些FOXO-蛋白质相互作用的性质，但这些知识对于理解FOXO蛋白质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蛋白如何传递关键的代谢信号并在不与DNA结合的情况下保持代谢健康。我们将鉴定和分析所有与FOXO结合并将其定位于靶基因的蛋白质。我们已经有候选蛋白质进行测试，因此我们将使用活细胞中的生物化学和蛋白质相互作用测定来更详细地研究这些相互作用的性质。我们还将操纵我们的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在维持代谢健康中重要的下游过程。总之，这些知识将使我们能够充分认识这些临床相关的转录调节因子在协调适当的代谢反应中的作用。异常的FOXO活性与代谢疾病有关，但直接针对FOXO的治疗很难实施，因为它有许多不同的功能。该项目是确定新药物靶点的重要阶段，这些靶点可用于治疗许多与代谢健康不良有病理联系的疾病，从而促进整个生命过程中的人类健康和福祉。

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.