A strategy for discovery of endocrine interactions

项目总结/摘要 我们开发了一个生物信息学框架，该框架使用多组织表达阵列， 资源统计排名和功能注释内分泌轴。通过将此方法应用于表达式 在杂交小鼠多样性小组（HMDP）中，我们鉴定了许多已知的和几种新的组织间 电路.我们通过揭示一种新的脂肪-骨骼肌内分泌途径进一步展示了这种方法的实用性。 轴，显示出作为小鼠和人类代谢综合征的治疗靶点的前景。功能 实验表明脂肪来源的脂质运载蛋白-5（LCN 5）足以增强骨骼肌线粒体 活性和基因表达。当在小鼠模型中过表达时，所分泌的肽防止和 通过胰岛素和葡萄糖耐量测定，挽救饮食诱导的代谢综合征。我们也证明了 该蛋白质的人类直向同源物足以增强类似氧化和生物合成基因的表达 在人体肌肉细胞中。我们进一步扩展该方法以鉴定脂肪源性Inter α-胰蛋白酶抑制剂5 （Itih 5）作为心肌细胞功能的保守调节剂。具体来说，小鼠和人类的相关数据 机制研究表明ITIH 5是心肌细胞肥大的抑制因子。这项提案的目的是 1）机械地剖析脂质运载蛋白-5/6如何增强小鼠骨骼肌线粒体活性， 2）利用全球和有针对性的研究来了解ITIH 5减少的生物过程 在生理和病理生理状态下的心脏肥大。

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.