How does diet improve metabolic health? Dissecting bioenergetic pathways altered by diet using genomic approaches (TRAKA_F17DTP1)

富含西兰花的饮食与降低患一系列慢性病的风险有关，如心血管疾病和某些癌症。我们最近表明，食用西兰花丰富的饮食可以降低低密度脂蛋白胆固醇和空腹血糖水平，这表明西兰花调节中心代谢途径的方式可能防止慢性疾病的发展。西兰花含有丰富的萝卜硫素，这是一种含硫的葡萄糖苷，虽然本身并不具有生物活性，但很容易在肠道中代谢成具有生物活性的萝卜硫素。通过使用细胞和动物模型，萝卜硫素与关键转录因子-核因子-红系2样蛋白2(NRF2)的激活有关，NRF2负责通过与抗氧化剂基因启动子内的特定元件结合上调一系列抗氧化剂基因。最近的证据表明，NRF2也可能在调节能量代谢方面发挥作用，尽管还没有得到充分的研究，但这可能是富含西兰花的饮食促进健康的机制。该博士项目将重点研究NRF2激活在调节维持健康的肝脏代谢途径变化中的重要性。该项目将首先使用全基因组测序技术来确定西兰花生物活性物质和NRF2改变的转录级联，并了解它们对脂肪酸代谢和细胞生物能量学的影响。还将有机会通过基因组编辑设计出新的基因敲除人类细胞，以具体了解Nrf2在调节饮食生物活性的代谢调节中的重要性。

Broccoli-rich diets have been associated with reduced risk of developing a range of chronic diseases, such as cardiovascular disease and certain cancers. We have recently showed that consumption of broccoli rich diets reduces LDL cholesterol and fasted glucose levels, which suggests that broccoli modulates central metabolic pathways in a manner that may protect against development of chronic diseases. Broccoli is rich in glucoraphanin, a sulphur-containing glucoside that though not bioactive itself is readily metabolised in the gut to bioactive sulforaphane. By using cell and animal models sulforaphane has been linked to the activation of a key transcription factor, nuclear factor-erythroid 2 like 2 (NRF2), which is responsible for upregulating a host of antioxidant genes by binding to a defined element within their promoter. Recent evidence suggests that NRF2 may also play a role in modulating energy metabolism that though under-explored is likely the mechanism by which broccoli-rich diets promote good health. This PhD project will focus on studying the importance of NRF2 activation in mediating the changes in liver metabolic pathways that can maintain health. This project will, first, use whole genome sequencing techniques to identify the transcriptional cascades that are altered by broccoli bioactives and NRF2 and understand their effect on fatty acid metabolism and cellular bioenergetics. There will also be opportunity to engineer novel genetic knockout human cells through genome editing to specifically understand the importance of nrf2 in mediating metabolic regulation by dietary bioactives.