Conserved role of uric acid and purine metabolites in longevity and healthspan

项目总结/摘要 尿酸会随着年龄增长和营养丰富的饮食而增加1 -9。高尿酸血症与高尿酸血症相关 死亡风险和与衰老相关的疾病，如高血压、血脂异常、2型糖尿病、心血管疾病 疾病，代谢综合征和痛风性关节炎的临床队列研究。血清或尿UA水平升高， 在进化过程中，尿酸酶的丢失是人类的结果， 人类食用丰富的饮食，高尿酸血症困扰着超过20%的美国人口10，11。 尽管是发病率增加的危险因素，但尿酸增加的遗传和机械原因 水平不太清楚。未知遗传关联的测试以前已经使用 几个人类队列发现与血清尿酸水平或痛风相关的基因，但在体内测试， 还没有被用来验证这些基因。这主要是由于缺乏适用的动物模型。 因此，我们建立了一个利用尿酸酶敲低的果蝇模型， 程度.尿酸酶的抑制导致了饮食依赖性的寿命缩短和尿酸的积累 结石胰岛素样信号（ILS）通路基因的遗传和药理学抑制可降低UA 荷载和结核形成。此外，ILS在调节UA中的保守作用得到了以下研究的支持： 显示ILS基因IGFR 1、AKT 2和FOXO 3中的SNP与调节血清UA相关的数据 水平或痛风。为了确定尿酸的其他调节因子，我进行了全基因组关联， DGRP中约150种不同蝇株中尿酸和上游嘌呤途径代谢物的研究（GWAS） 收集两种不同的饮食。我们验证了5个调节尿酸积累的新基因。 在目标1中，我将研究ILS通路的作用，该通路已在人类队列中被鉴定为调节剂 尿酸ILS是一个高度保守的信号级联，当果蝇被喂食高蛋白质时， 饮食.我假设尿酸水平是通过嘌呤稳态的多方面调节来介导的 通过FOXO和下游作用于ROS产生。在目标2中，我将描述候选人的特点， 一项遗传筛选发现了果蝇遗传学中嘌呤代谢的新调节剂， 参考样本组（DGRP）苍蝇采集。我将描述它们在高尿酸血症介导的结石中的作用 形成，健康，和寿命在我们的苍蝇模型。我还将与Giacomini实验室合作， 候选蝇基因的人类直向同源物也调节人类的高尿酸血症。我的工作会更有帮助 了解ILS和嘌呤代谢如何影响尿酸水平和寿命，确定治疗目标 以减少人类高尿酸血症相关的病理。

PROJECT SUMMARY/ ABSTRACT Uric acid builds up with both age and a nutrient-rich diet1-9. Elevated uric acid is associated with higher all-cause mortality risk and aging-related diseases such as hypertension, dyslipidemia, type-2 diabetes, cardiovascular disease, metabolic syndrome and gouty arthritis in clinical cohort studies. Elevated serum or urinary UA level in humans is a consequence of the loss of the enzyme uricase, during evolution, further augmented by the consumption of an enriched diet in humans, with hyperuricemia afflicting over 20% of the US population10,11. Despite being a risk factor for increased morbidity, the genetic and mechanistic causes of increasing uric acid levels are not well known. Tests of unknown genetic associations have previously been performed utilizing several human cohorts to find genes associated with either serum uric acid levels or gout, but in vivo tests have not been performed to validate these genes. This is primarily due to the lack of applicable animal models. Therefore, we established a Drosophila melanogaster model using Uricase knockdown, which increases UA levels. The inhibition of uricase led to both a diet-dependent shortening of lifespan and a buildup of UA concretions. Genetic and pharmacological inhibition of insulin-like signaling (ILS) pathway genes reduced UA load and concretion formation. Furthermore, a conserved role for the ILS in modulating UA was supported by data showing that SNPs in the ILS genes IGFR1, AKT2, and FOXO3 are associated with regulating serum UA levels or gout in humans. To identify other regulators of uric acid, I performed a Genome-Wide Association Study (GWAS) of uric acid and upstream purine pathway metabolites in ~150 different fly strains from the DGRP collection on two different diets. We validated 5 novel genes that modulate uric acid accumulation. In Aim 1 I will examine the role of the ILS pathway which has been identified in human cohorts as a modulator of uric acid. ILS is a well-conserved signaling cascade that is activated when Drosophila is fed a high protein diet. I hypothesize that levels of uric acid are mediated through a multifaceted adjustment of purine homeostasis acting through FOXO and downstream effects on ROS production. In Aim 2 I will characterize candidates from a genetic screen that has uncovered novel modulators of purine metabolism in the Drosophila Genetic Reference Panel (DGRP) collection of flies. I will characterize their role in hyperuricemia mediated concretion formation, healthspan, and lifespan in our fly model. I will also collaborate with the Giacomini lab to determine if human orthologs of candidate fly genes also modulate hyperuricemia in humans. My work will help better understand how ILS and purine metabolism influence uric acid levels and lifespan, identifying therapeutic targets to reduce human hyperuricemia-related pathologies.