Human tissue specific age-related gene expression changes, their genetic regulations and the link to human diseases

项目摘要 了解人类衰老需要我们直接用人类进行实验。这可能具有挑战性 由于伦理障碍、高成本、长的人类寿命和若干其他因素。另一方面， 人类基因组数据已经出现，其中一些具有突出的潜力，可以重新定位， 老化研究利用现有的人类数据进行老龄化研究提供了一个经济有效的，时间- 节省解决方案，以克服与人体实验相关的许多障碍。我们建议深入 分析一个非常独特和前所未有的大规模人类基因组数据集，用于衰老研究。这 从GTEx（组织表达基因型）项目生成的数据集代表了一个难得的机会， 在多组织水平上研究人类衰老基因表达和遗传学。我们建议在四个具体领域开展工作， 目的：首先，我们将确定人类衰老基因在40多种组织类型中的表达特征。对于许多 组织，这是第一次揭示其衰老基因表达变化模式。我们亦会研究 疾病和性别对这些衰老基因表达的影响，并从模型中寻找保守的衰老机制 有机体对人类其次，早期研究表明，人体不同部位的年龄不同， 速率，但不知道不同组织的生物年龄是否处于高阶协调下。我们的工作 是为了证实我们以前关于组织间协调老化的发现。我们将 还可以测试组织共老化是否与疾病共病相关。第三，我们将研究基因调控， 不同组织中与年龄相关的基因表达。我们将测试是否与衰老基因相关的遗传变异 表达也可能与人类寿命或与年龄有关的疾病有关。第四，我们将选择顶级 变体，并通过实验验证基因表达的因果调节。我们相信所有这些问题 对人类衰老研究很重要;这些问题的答案将大大帮助我们更好地 了解人类衰老并帮助转化研究。

Project Summary Understanding human aging requires us to perform experiments directly with human. This can be challenging due to ethical barriers, high cost, long human lifespan and several other factors. On the other hand, a deluge of human genomic data have emerged and some of them have outstanding potentials to be repositioned for aging research. Leveraging existing human data for aging research provides an economically efficient, time- saving solution to overcome the many obstacles associated with human experiments. We propose to go deep in analyzing a very unique and unprecedented large scale human genomic dataset for aging research. This dataset as generated from GTEx (Genotype of Tissue Expression) project represents a rare opportunity for studying human aging gene expressions and genetics at multi-tissue level. We propose to work on four specific aims: first, we will define human aging gene expression signatures in more than 40 tissue types. For many tissues, this is the first time to reveal their aging gene expression change patterns. We will also investigate disease and sex influence on these aging gene expression and find conserved aging mechanisms from model organisms to human. Second, early studies have shown that different parts of human body age at different rates, but it is unknown if the biological ages of different tissues are under higher order coordination. Our work is to investigate on this topic to confirm our previous finding on the coordinated aging among tissues. We will also test if tissue co-aging correlates with disease comorbidity. Third, we will look into the genetic regulation on age-related gene expression in various tissues. We will test if genetic variants associated with aging gene expression could also be associated with human longevity or age-related diseases. Fourth, we will select top variants and experimentally validate the causal regulation on gene expression. We believe all these questions are important for human aging research; the answers to these questions will significantly help us to better understand human aging and help translational research.