A strategy for discovery of endocrine interactions

发现内分泌相互作用的策略

基本信息

批准号：
10055105
负责人：
Marcus Michael Seldin
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-03 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055105
关键词：
Acute Adipose tissue Biogenesis Bioinformatics Biological Process Biology Calcineurin Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell surface Cells Collaborations Communication Data Data Set Dependovirus Development Diabetes Mellitus Diet Dissection Endocrine Epitopes Expression Profiling Gene Chips Gene Expression Genes Goals Heart Heart Hypertrophy Homeostasis Human Hybrids Hypertrophy Insulin Resistance Investigation Isoproterenol Link Mass Spectrum Analysis Measures Mediating Metabolic Metabolic syndrome Methods Modeling Mus Muscle Cells Muscle Mitochondria Pathway interactions Peptides Pharmacology Physiological Population Process Proteins Public Health Recombinant Proteins Regulation Resources Signal Transduction Skeletal Muscle Small Interfering RNA Starvation Suggestion System Therapeutic Time Tissues Transcript Translating adipokines career crosslink experimental study glucose tolerance improved in vivo insulin tolerance inter-alpha-inhibitor knock-down mouse model novel novel therapeutics overexpression oxidation prevent receptor response screening therapeutic target transcriptome sequencing

项目摘要

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.

项目概要/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和公开可用的通过将此方法应用于表达，对内分泌轴进行专门排序和功能注释。通过混合小鼠多样性面板 (HMDP) 中的配置文件，我们识别出许多已知的和一些新颖的组织间我们通过发现一种新的脂肪到骨骼肌内分泌进一步展示了这种方法的实用性。轴有望成为小鼠和人类代谢综合征的治疗靶点。实验表明脂肪来源的 Lipocalin-5 (LCN5) 足以增强骨骼肌线粒体当在小鼠模型中过度表达时，分泌的肽可以防止和基因表达。通过胰岛素和葡萄糖耐量来衡量，可以挽救饮食引起的代谢综合征。我们还证明了这一点。该蛋白质的人类直系同源物足以增强类似氧化和生物发生基因的表达我们进一步扩展了这种方法来鉴定脂肪来源的间 α-胰蛋白酶抑制剂 5。（Itih5）作为心肌细胞功能的保守调节剂，具体而言，小鼠和人类的相关数据。机制研究表明ITIH5作为心肌细胞肥大的抑制剂是该提案的目标。 1) 从机制上剖析 Lipocalin-5/6 如何增强小鼠骨骼肌线粒体活性，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和病理生理状态下的心脏肥大。