A strategy for discovery of endocrine interactions

项目摘要/摘要 我们开发了一个使用多组织表达阵列的生物信息学框架，并公开提供 对内分泌轴进行统计排名和功能注释的资源。通过将此方法应用于表达式 在杂交小鼠多样性小组(HMDP)中，我们识别了许多已知的和几个新的组织间 电路。通过揭示一种新的脂肪到骨骼肌的内分泌，我们进一步展示了这种方法的有效性。 Axis在小鼠和人类身上都显示出作为代谢综合征治疗靶点的前景。功能性 实验表明，脂肪衍生的Lipocalin-5(LCN5)足以增强骨骼肌线粒体 活性和基因表达。当在小鼠模型中过度表达时，分泌的多肽可以防止和 挽救以胰岛素和葡萄糖耐量为标准的饮食诱导的代谢综合征。我们还表明， 人类同源的蛋白质足以增强类似的氧化和生物发生基因的表达 在人类肌肉细胞中。我们进一步扩展该方法以鉴定脂肪来源的α-胰酶抑制物5 (Itih5)作为一种保守的心肌细胞功能调节因子。具体地说，老鼠和人类的相关数据 机制研究表明，ITIH5是一种抑制心肌细胞肥大的药物。这项提案的目标是 1)机械解剖Lipocalin-5/6是如何增强小鼠骨骼肌线粒体活性的 人类和2)利用全球和有针对性的研究来了解ITIH5减少的生物过程 生理性和病理生理学状态下的心肌肥厚。

Project Summary/Abstract We developed a bioinformatics framework which uses multi-tissue expression arrays and publicly available resources to statistically rank and functionally annotate endocrine axes. By applying this method to expression profiles within the Hybrid Mouse Diversity Panel (HMDP), we identify many known and several novel inter-tissue circuits. We further show the utility of this approach by uncovering a new adipose-to-skeletal muscle endocrine axis which shows promise as a therapeutic target for metabolic syndrome in both mice and humans. Functional experiments show adipose-derived Lipocalin-5 (LCN5) is sufficient to enhance skeletal muscle mitochondrial activity and gene expression. When overexpressed in a mouse model, the secreted peptide prevents and rescues diet-induced metabolic syndrome as measured by insulin- and glucose- tolerance. We also show that the human orthologue of the protein is sufficient to enhance expression of similar oxidation and biogenesis genes in human muscle cells. We further expand this method to identify adipose-derived Inter α-trypsin inhibitor 5 (Itih5) as a conserved regulator of cardiomyocyte function. Specifically, correlative data in mice and humans and mechanistic studies show ITIH5 as a suppressor of cardiomyocyte hypertrophy. The goal of this proposal is to 1) Mechanistically dissect how Lipocalin-5/6 enhances skeletal muscle mitochondrial activity in mice and humans and 2) Utilize both global and targeted studies to understand biologic processes by which ITIH5 reduces cardiac hypertrophy in a physiologic and pathophysiologic state.