Combining experiments of man and nature to target human insulin resistance

摘要 胰岛素抵抗是慢性疾病的主要原因，包括2型糖尿病（T2 D）、心脏病发作、中风 和癌症只有一类药物，噻唑烷二酮类（TZDs），专门针对胰岛素抵抗 主要通过激活脂肪细胞中的转录因子PPARG。虽然TZDs已被临床证明 有效预防2型糖尿病、心脏病发作和中风，但严重的副作用限制了它们的临床应用。新 需要对抗胰岛素抗性的治疗靶点。从理论上讲，基因表达的变化引起的 通过TZD治疗可以挖掘新的胰岛素增敏效应，但TZD改变了 数百个基因。这些必须通过功能性调查来筛选， 相关的或有毒的旁观者。标准的基于实验室的功能检查需要侵入性 在模型系统中的生理测量是难以缩放的。即使潜在的胰岛素 在实验室中验证了致敏效应基因，证明其与人胰岛素敏感性相关 药物开发和人体试验是另一个可扩展性差的过程，通常会导致失败 因为缺乏功效。然而，最近积累的基因组序列在大，临床特征 人口显示，大自然已经进行了无数的人类试验的形式，数百万的自然 发生的，改变蛋白质的遗传变异分散了基因组中几乎每个基因的通量。的关键 解锁这两个机会：1）从TZD治疗中鉴定新的候选基因，2）利用 用于评估治疗潜力的自然临床试验是高通量功能测定。在这 应用，我们建议利用新开发的大规模平行脂肪细胞分化/脂质 在整合基因组方法中的累积测定，以： 目的1：快速分选TZD改变的基因作为胰岛素增敏效应物的可能性， 目标2：使用来自以下数据的已确定的和新的人类治疗潜力候选物 10万个测序个体。 这项工作将产生一个系统的解剖TZDs的治疗效果，以确定新的胰岛素 敏感性基因，并直接评估人类四种 这些基因。

Abstract Insulin resistance is a major cause of chronic diseases including type 2 diabetes (T2D), heart attacks, strokes and cancer. Only one class of medications, thiazolidinediones (TZDs), specifically targets insulin resistance primarily by activating the transcription factor PPARG in adipocytes. While TZDs have proven clinically effective in preventing T2D, heart attacks and strokes, serious side effects have limited their clinical use. New therapeutic targets to combat insulin resistance are needed. In theory, the gene expression changes caused by TZD-treatment could be mined for novel insulin-sensitizing effectors, but TZDs alter the expression of hundreds of genes. These must be sifted by functional investigation for causal effectors versus merely correlated or toxic bystanders. Standard laboratory-based functional investigation requires invasive physiological measurements in model systems that are difficult to scale. Even when a potential insulin sensitizing effector gene is validated in the lab, credentialing its relevance to human insulin sensitivity necessitates drug development and human trials, another poorly scalable process that usually results in failure for lack of efficacy. However, the recent accumulation of genome sequences in large, clinically characterized populations has revealed that nature has performed countless human trials in the form of millions of naturally occurring, protein-altering genetic variants scattered throughput almost every gene in the genome. The key to unlocking both these opportunities: 1) identifying novel candidate genes from TZD treatment and 2) leveraging nature’s clinical trials for assessing therapeutic potential, are high-throughput functional assays. In this application, we propose to utilize a newly developed massively parallel adipocyte differentiation/ lipid accumulation assay in an integrative genomic approach to: Aim 1: Rapidly sort TZD-altered genes for likelihood of being insulin sensitizing effectors and Aim 2: Credential already identified and novel candidates for therapeutic potential in humans using data from 100,000 sequenced individuals. This work will produce a systematic dissection of the therapeutic effect of TZDs to identify novel insulin sensitivity genes and directly assess the therapeutic potential of modulating function in humans for four of these genes.