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 due to its role in the degradation of TNFα mRNA, thus very few studies have assessed the role of TTP in metabolism despite its original discovery as an insulin-inducible gene. We recently showed that TTP regulates cellular iron by conserving this metal for essential proteins. In addition, our recent studies suggest that TTP regulates fatty acid (FA) metabolism, and binds to and regulates the mRNAs of key proteins in this process, i.e., peroxisome proliferator-activated receptor (PPAR)-α. The central hypothesis of this proposal is that TTP regulates cardiac FA metabolism through downregulation of PPARα metabolism. We also propose that deletion of TTP is protective against the development of heart failure (HF). In Aim 1, we will assess whether TTP regulates cardiac FA metabolism by binding to PPARα mRNA and promoting its degradation. We will assess FA metabolism in hearts from cardiac-specific TTP KO (csTTP-KO) mice, and will determine whether these changes are through PPARα. We will also assess whether TTP directly regulates PPARα mRNA by performing deletion studies of its 3’-UTR AREs, RNA co-immunopreciptation (co-IP), and mRNA stability assays. In Aim 2, we will determine whether TTP plays a role in the development of HF and whether this is dependent on FA metabolism and regulation of PPARα. We will subject csTTP-KO mice to pressure overload and coronary ligation and will assess their cardiac function. We will also cross csTT-KO mice with PPARα KO mice and will determine whether deletion of PPARα reverses the effects of TTP deletion on cardiac metabolism and cardiac function.
|Effective start/end date||7/1/17 → 6/30/19|
- American Heart Association (17GRNT33670353)
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.