Chronic inflammation is a principal cause of atherosclerosis and other vascular diseases. Inflammation is an orchestrated response to trauma incited by tissue injury or microbial invasion of the host. The inflammatory response is initiated by cytokines that induce cascades of signaling events culminating in the expression of new gene products, some of them toxic to invading organisms. Uncontrolled production or accumulation of inflammatory products can be injurious to the host organism. Mechanisms have evolved that limit the production of these products and permit resolution of the inflammatory response. The central hypothesis of this continuing Program Project is that pro- and anti-inflammatory processes in vascular cells are tightly regulated by endogenous signaling pathways, and their dysregulation contributes to vascular diseases such as atherosclerosis. We will investigate this hypothesis through three highly focused, but well-integrated projects led by a team of accomplished experts in diverse areas of vascular inflammation. In Project 1, Dr. Xiaoxia Li investigates the macrophage signaling pathways initiated by the interleukin-1R (IL-1 receptor)/TLR (Toll-like receptor) superfamily which can lead to either a pro-inflammatory, transcriptional program of gene expression, or an anti-inflammatory, post-transcriptional program. The theme of pro- and anti-inflammation, and also post-transcriptional regulation, continues in Project 2, led by Dr. Paul Fox, which focuses on a distinct post-transcriptional mechanism in monocyte/macrophages in which interferon-??induces phosphorylation- dependent formation of a complex that binds select inflammatory transcripts and inhibits their translation. The goal of Project 3, led by Dr. Paul DiCorleto, is to understand the role of the tumor necrosis factor receptor p75 and the transcription factor HOXA9 in the transcriptional regulation of pro-inflammatory genes in endothelial cells. Three scientific cores (Cell Culture, Atherosclerosis and Lipoprotein Analysis, and Macromolecular Interaction) and an Administration Core will provide multi-project support, expertise, and service in a cost-effective manner, which will significantly strengthen each investigator's research effort.
Inflammation is an underlying cause of vascular diseases such as atherosclerosis. The goal of this Program Project is to understand the basic cellular and molecular mechanisms that induce, sustain, and resolve inflammation in two types of vascular cells - the endothelial cell that lines all blood vessels and the macrophage that specifically enters these vessels as part of the inflammatory response. A deeper understanding of inflammatory pathways is necessary to understand vascular disorders. Knowledge of these pathways may lead to new targets for the development of novel anti-inflammatory therapies.
|Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365|
|Robinet, Peggy; Milewicz, Dianna M; Cassis, Lisa A et al. (2018) Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 38:292-303|
|Zhang, Cun-Jin; Wang, Chenhui; Jiang, Meiling et al. (2018) Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. Nat Commun 9:2745|
|Han, Juying; Enyindah-Asonye, Gospel; Lin, Feng et al. (2018) CD6 expression has no effect on atherosclerosis in apolipoprotein E-deficient mice. BMC Res Notes 11:229|
|Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730|
|Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2018) The GAIT translational control system. Wiley Interdiscip Rev RNA 9:|
|Hai, Qimin; Ritchey, Brian; Robinet, Peggy et al. (2018) Quantitative Trait Locus Mapping of Macrophage Cholesterol Metabolism and CRISPR/Cas9 Editing Implicate an ACAT1 Truncation as a Causal Modifier Variant. Arterioscler Thromb Vasc Biol 38:83-91|
|Eswarappa, Sandeep M; Potdar, Alka A; Sahoo, Sarthak et al. (2018) Metabolic origin of the fused aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase. J Biol Chem 293:19148-19156|
|Halawani, Dalia; Gogonea, Valentin; DiDonato, Joseph A et al. (2018) Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains. J Biol Chem 293:8843-8860|
|Zhou, Hao; Bulek, Katarzyna; Li, Xiao et al. (2017) IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs. Elife 6:|
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