The long-term goal of Project 2 is to elucidate the role of ribosomal protein L13a in post-transcriptional regulation of inflammatory gene expression in monocyte/macrophages. Interferon (IFN)-gamma is the classic activator of monocyte/macrophages;it induces rapid transcription of inflammatory growth factors, proteases, chemokines, and generators of radical species. If unregulated, this process becomes chronic and monocyte/macrophage products accumulate, damage host tissue, and contribute to chronic disorders of blood vessels, e.g., atherosclerosis. We have discovered a novel translational control pathway that acts as an endogenous regulator of the inflammatory response. In myeloid cells, IFN-gamma induces assembly of the IFN-Gamma-Activated Inhibitor of Translation (GAIT) complex, which binds an RNA element in the 3?untranslated region of pro-inflammatory target mRNAs, and inhibits their translation. In Preliminary Studies we show that one GAIT protein, L13a, has a critical role in the GAIT system: its function is regulated by phosphorylation, it induces conformational changes in other GAIT proteins to regulate target mRNA recognition, and by interaction with eIF4G it is responsible for the observed translational silencing. Recently, we have shown that stress can alter GAIT system activity and influence inflammatory gene expression. Based on these results, we propose the following hypothesis: IFN-gamma-dependent phosphorylation of L13a induces a conformational change that facilitates its release from the 60S ribosomal subunit, formation of the GAIT complex, and binding to eIF4G to cause translational silencing of inflammatory transcripts;moreover, physiological stress can alter GAIT system function and inflammatory gene expression. We will test this hypothesis by pursuit of three Specific Aims.
In Aim 1 we will determine the mechanism of inducible release of L13a from ribosome in the response to inflammatory stimulus.
In Aim 2 we will determine L13a interactions required for GAIT complex assembly and silencing of inflammatory gene expression.
In Aim 3 we will determine the mechanisms by which stress alters GAIT complex function and inflammatory gene expression.
Our studies will elucidate a new pathway that regulates the synthesis of inflammatory proteins by macrophages, an important process in the development of vascular diseases such as atherosclerosis. The pathway under investigation contributes to the limitation and resolution of chronic inflammation, an important causative factor in disease progression. A deeper understanding of inflammatory stop pathways is important because defects in these pathways can contribute to vascular disorders, and because the pathway itself may present alternative targets for development of novel anti-inflammatory therapeutics.
|Tang, W H Wilson; Wang, Zeneng; Shrestha, Kevin et al. (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21:91-6|
|Grodin, Justin L; Hammadah, Muhammad; Fan, Yiying et al. (2015) Prognostic value of estimating functional capacity with the use of the duke activity status index in stable patients with chronic heart failure. J Card Fail 21:44-50|
|Grodin, Justin L; Neale, Sarah; Wu, Yuping et al. (2015) Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. Am J Med 128:276-82|
|Christian, Abigail J; Lin, Hongqiao; Alferiev, Ivan S et al. (2014) The susceptibility of bioprosthetic heart valve leaflets to oxidation. Biomaterials 35:2097-102|
|Shao, Zhili; Zhang, Renliang; Shrestha, Kevin et al. (2014) Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure. Am J Cardiol 113:1839-43|
|Brown, J Mark; Hazen, Stanley L (2014) Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 25:48-53|
|Ghosh, Arnab; Stasch, Johannes-Peter; Papapetropoulos, Andreas et al. (2014) Nitric oxide and heat shock protein 90 activate soluble guanylate cyclase by driving rapid change in its subunit interactions and heme content. J Biol Chem 289:15259-71|
|Brown, J Mark; Hazen, Stanley L (2014) Seeking a unique lipid signature predicting cardiovascular disease risk. Circulation 129:1799-803|
|Ray, Partho Sarothi; Fox, Paul L (2014) Origin and evolution of glutamyl-prolyl tRNA synthetase WHEP domains reveal evolutionary relationships within Holozoa. PLoS One 9:e98493|
|Hammadah, Muhammad; Fan, Yiying; Wu, Yuping et al. (2014) Prognostic value of elevated serum ceruloplasmin levels in patients with heart failure. J Card Fail 20:946-52|
Showing the most recent 10 out of 177 publications