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Principal Investigator: Hossein Ardehali
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $566,077
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <(TNF)-α><3' Untranslated Regions><3'UTR><Acids><Address><Animal Model><Animal Models and Related Studies><Autoregulation><Binding><Binding Proteins><Body Tissues><Branched-Chain Amino Acids><Cachectin><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Catabolism><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Co-Immunoprecipitations><Collaborations><Complex><Data><Defect><Dehydrogenases><Developed Countries><Development><Disease><Disorder><Drugs><Elements><Epidemic><Fatty Acid Metabolism Pathway><Fatty Acids><G0-G1 switch regulatory protein 24><GOS24 protein><Genes><Genetic study><Health><Heart><Heart Muscle Cells><Heart failure><Heart myocyte><Homeostasis><Human><Humulin R><Impairment><Industrialized Countries><Industrialized Nations><Inflammation><Inflammatory><Insulin><Intermediary Metabolism><Ischemia><KO mice><Keto Acids><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lipids><Macrophage-Derived TNF><Measures><Mediating><Medication><Messenger RNA><Metabolic Processes><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monocyte-Derived TNF><Murine><Mus><Non-Polyadenylated RNA><Novolin R><NuP475 protein><Null Mouse><Oxidoreductase><Oxidoreductase Gene><PPAR alpha><PPAR-α><PPARalpha><PPARα><Pathology><Pathway interactions><Perfusion><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Pharmaceutical Preparations><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Physiological Homeostasis><Process><Protein Binding><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein phosphatase><Proteins><RNA><RNA Gene Products><Reductases><Regular Insulin><Regulation><Ribonucleic Acid><Role><Stress><Subcellular Process><System><TIS11 protein><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TTP protein><Testing><Tissues><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><ZFP36 protein><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><amino acid metabolism><aorta constriction><bound protein><branched amino acids><branched chain alpha ketoacid dehydrogenase><branched chain fatty acid><branched chain α ketoacid dehydrogenase><cardiac failure><cardiac function><cardiac metabolism><cardiac preservation><cardiomyocyte><clinical relevance><clinically relevant><developed country><developed nation><developed nations><developmental><drug discovery><drug/agent><fat metabolism><fatty acid metabolism><fatty acid oxidation><function of the heart><heart function><heart metabolism><heart preservation><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><improved><induced human pluripotent stem cells><ketoacid><knock-down><knockdown><lipid metabolism><mRNA><mRNA Degradation><mRNA Transcript Degradation><model of animal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oxidation><pathway><posttranscriptional><preservation><pressure><response><side effect><social role><systemic inflammation><systemic inflammatory response><tristetraprolin><uptake>