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Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure

mRNA结合蛋白tristetraprolin在心脏mRNA调节和心力衰竭发展中的作用

基本信息

批准号：
10544156
负责人：
Hossein Ardehali
金额：
$ 57.76万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544156
关键词：
3&apos Untranslated Regions Acids Address Amino Acids Animal Model Binding Binding Proteins Branched-Chain Amino Acids Cardiac Cardiac Myocytes Catabolism Cell physiology Clinical Co-Immunoprecipitations Collaborations Complex Data Defect Developed Countries Development Disease Elements Epidemic Fatty Acids Genes Genetic study Health Heart Heart failure Homeostasis Human Impairment Inflammation Inflammatory Insulin Ischemia Keto Acids Knock-out Knockout Mice Knowledge Link Lipids Measures Mediating Messenger RNA Metabolic syndrome Metabolism Modeling Mus Oxidoreductase PPAR alpha Pathology Pathway interactions Perfusion Pharmaceutical Preparations Process Protein phosphatase Proteins RNA Regulation Role Stress System TIS11 protein TNF gene Testing Tissues Zinc Fingers amino acid metabolism aorta constriction branched chain alpha ketoacid dehydrogenase branched chain fatty acid clinically relevant drug discovery fatty acid metabolism fatty acid oxidation heart function heart metabolism heart preservation improved induced pluripotent stem cell knock-down lipid metabolism mRNA Transcript Degradation new therapeutic target novel oxidation posttranscriptional preservation pressure response side effect systemic inflammatory response uptake

项目摘要

Heart failure (HF) is a major health epidemic in developed countries, however, its underlying pathology is not well characterized. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich elements (ARE) in the 3’-untranslated region (UTR) of target mRNA molecules, and induces their degradation. Global TTP knockout (KO) mice display systemic inflammation, since TNFα mRNA is normally degraded by TTP, and deletion of TTP leads to elevated TNFα levels. Thus, very few studies have assessed the role of TTP in metabolism despite its original discovery as an insulin-inducible gene, and genetic studies linking TTP to metabolic syndrome. We are addressing this fundamental gap in knowledge, and our strong preliminary data suggest critical activities by TTP in cardiac metabolism and the development of HF. Specifically, we have shown that TTP inhibits fatty acid (FA) and branched-chain amino acid (BCAA) metabolism (independent of its effects on inflammation), and reduces the mRNA levels of key proteins in these processes, i.e., peroxisome proliferator-activated receptor (PPAR)-α and branched-chain α–ketoacid acid dehydrogenase complex (BCKDC)-E2 subunits. The central hypothesis of this proposal is that TTP inhibits cardiac FA and BCAA metabolism by binding to and degrading PPARα and BCKDC-E2 mRNAs, and that TTP exacerbates the development of HF by impairing FA and BCAA metabolism. In Aim 1, we will assess whether TTP inhibits cardiac FA metabolism by binding to PPARα mRNA and promoting its degradation. We will assess whether TTP binds to PPARα mRNA by performing RNA co-immunopreciptation (co-IP) and deletion studies of PPARα 3’-UTR AREs. We will also measure FA uptake and metabolism in the hearts from cardiac-specific TTP KO (csTTP-KO) mice, and will determine whether these changes are through PPARα using TTP/PPARα double KO mice. In Aim 2, we will determine whether TTP decreases BCAA catabolism through binding and degradation of BCKDC-E2 mRNA. We will first determine whether TTP binds BCKDC-E2 mRNA by performing RNA co-IP and deletion studies on BCKDC-E2 3’-UTR AREs. We will also measure BCAA levels and BCKDC activity in heart tissue from csTTP-KO mice. To demonstrate whether the reduction in BCAA catabolism with TTP KO is through BCKDC-E2, we will perform similar studies with knockdown of TTP and BCKDC-E2. In Aim 3, we will determine whether TTP has detrimental effects on the heart under stress conditions, and whether this depends upon impaired FA and BCAA metabolism. We will subject csTTP-KO mice to pressure overload and ischemia, then assess their cardiac function and metabolism. To determine the role of PPARα and BCKDC in this process, we will use csTTP/PPARα double KO mice and will cross csTTP-KO with protein phosphatase 2Cm KO mice (which have reduced BCKDC activity), and assess cardiac response to stress. We will also show our studies to develop novel drugs that target TTP without inducing inflammation, providing potential clinical implications for Aim 3. These studies will improve our understanding of cardiac metabolism, and may lead to new avenues for treatment of HF.

心衰（HF）在发达国家是一种主要的健康流行病，然而，其潜在的病理却不是