Modelling Sex Dependent Differences in Human Liver Disease using Stem Cell-Derived Models and Organ on a Chip Devices

代谢综合征直接影响不同的疾病，如糖尿病、心脏病或腰部脂肪堆积，导致肝脏疾病，例如肝脂肪变性。肝脂肪变性可发展为非酒精性脂肪肝（NAFLD）。NAFLD通常发展为非酒精性脂肪性肝炎（NASH），引起组织纤维化，20%的病例可发展为肝硬化。NAFLD的易感性受体脂过多和胰岛素不敏感的影响。流行病学研究表明，性别和年龄差异是导致脂肪肝和代谢综合征的重要因素，这表明性激素在其中起着重要作用。因此，研究不同性激素在不同系统中的作用将有助于早期预测风险，并有助于在研究不足的科学领域建立模型。研究表明，年龄是NAFLD发生的一个重要因素，因为由于性激素缺乏，绝经前妇女比绝经后妇女更不容易发生NAFLD。此外，雄激素和雌激素调节脂质、葡萄糖和胆固醇稳态在男性和女性中是不同的。虽然睾酮可以保护男性免受肝脏脂肪堆积的影响，但对女性来说，它会促进脂肪堆积。雌激素对炎症反应有影响。总之，性激素在不同性别中有不同的作用，对年龄敏感。建立性别差异模型将帮助我们了解肝脏疾病的进展，从而制定新的治疗策略，如精确的激素治疗剂量。该项目的目的是确定非酒精性脂肪性肝病发展中性别依赖差异的分子基础，作为开发纠正异常表型的新疗法的基础。通过使用新的NAFLD模型，该模型采用多能干细胞衍生的肝细胞样细胞（HLCs），并将其暴露于生理相关水平的雄性激素、雌激素和生长激素中，将施加不同的环境条件（“脂肪”或正常饮食）。激素信号和脂肪变性的相互作用将在体外使用Hay教授实验室（爱丁堡大学再生医学中心）开发的半自动平台进行研究，重点关注肝细胞生物学的关键变化，包括肝脏代谢和功能、细胞活力、基因转录和因子分泌。在使用生物信息学和靶标识别技术进行深入分析后，这些研究中建立的性别特异性模型将使用器官芯片系统进一步完善。从静态和灌注培养中获得的基因调控数据集将被用作通过逆转脂肪变性和/或减少炎症基因表达来恢复肝细胞稳态的基础。研究将受益于与工业伙伴的密切合作，并有机会在不同的实验室工作，以获得广泛的方法和不同的工作环境的经验。

Metabolism syndrome directly influences different conditions such asdiabetes, heart disease or fat accumulation in individuals around the waist causing liver disease,for example, liver steatosis. Liver steatosis can progress into non-alcoholic fatty liver disease(NAFLD). NAFLD usually progresses into non-alcoholic steatohepatitis (NASH) causing tissuefibrosis and in 20% of the cases, cirrhosis of the liver. The susceptibility to NAFLD is impactedby excessive body fat and insulin insensitivity. Epidemiological studies show sex and agedifferences are important factors in developing fatty liver disease and metabolic syndrome,suggesting that sex hormones play important roles. Hence studying the effect of different sexhormones in different systems would cause an early risk prediction and would help to create amodel in the highly understudied scientific field.The studies show that age is an important factor in developing the NAFLD as premenopausalwomen are less likely to develop NAFLD than post-menopausal women due to sex hormonedeficiency. Moreover, androgens and oestrogens regulate lipid, glucose and cholesterolhomeostasis differently in men and women. Whilst testosterone protects males from fataccumulation in the liver, in females it promotes it. Oestrogens have an impact on theinflammatory response. In summary, sex hormones have different roles in different sexes thatare age-sensitive. Modelling sex differences would help us understand the progression of theliver disease, followed by new therapeutic strategies such as the precise dosage of hormonaltreatment.The aim of this project is to define the molecular basis of sex dependent differences in thedevelopment of non-alcoholic fatty liver disease as the basis for developing novel therapies tocorrect the aberrant phenotype. By using the novel NAFLD model that employs pluripotent stemcell derived hepatocyte like cells (HLCs) and exposing them to physiologically relevant levels ofandrogen, oestrogen and growth hormones, different environmental conditions ('fatty' or normaldiet) will be imposed. The interaction of hormone signaling and the development of steatosis willbe studied in vitro using a semi-automated platform developed in prof. Hay's lab (Centre ofRegenerative Medicine, University of Edinburgh), with a focus on key changes in liver cellbiology, including hepatic metabolism and function, cell viability, gene transcription and factorsecretion. Following in-depth analysis using bioinformatics coupled with target identification, thesex specific models developed from these studies will be further sophisticated using organ on achip systems. The gene regulatory datasets derived in static and perfused culture will be usedas a basis to restore hepatocyte homeostasis by reversing steatosis and/or reducinginflammatory gene expression. Studies will benefit from a close collaboration with an industrialpartner and an opportunity to work in different laboratories to gain experience in a broad rangeof methods and different working environments.