Dysregulated inflammation is important in the initiation and progression of atherosclerosis. In studies supported by this grant for the past 15 years, our laboratory has cloned one of the key inflammatory response genes, cyclooxygenase (COX)-2 and studied its role in the vascular system. Studies supported by this grant have also shown that the RNA binding protein HuR regulates the COX-2 gene at the post-transcriptional level. Given that HuR is a regulator of many inflammatory response genes, and its in vivo function is poorly understood, we developed Hur knockout mice and have begun to investigate its role in vivo. In this competitive renewal, we will focus on post- transcriptional regulation of vascular inflammation by the RNA regulator HuR. Thus the central hypothesis is that HuR-mediated post-transcriptional gene regulatory mechanisms in differentiated myeloid and endothelial cells restrains exaggerated inflammation and maintains normal vascular homeostasis. Aberrant regulation of HuR-mediated post-transcriptional mechanisms results in the cellular phenotypic change and accelerates the progression of atherosclerotic vascular disease. Therefore, we are proposing the following three specific aims. In the first specific aim, we will examine the hypothesis that HuR function in differentiated myeloid compartment controls monocyte/macrophage inflammatory phenotype. Second, we will examine the role of HuR-regulated post-transcriptional regulation on basal laminar shear stress induced and cytokine-induced inflammatory states of vascular endothelial cells. Third, we will examine the hypothesis that HuR- mediated post-transcriptional gene regulatory mechanisms restrains vascular inflammation and that absence of such mechanisms result in accelerated atherosclerosis in mouse models. We anticipate that these efforts will lead to new insights into our understanding of atherosclerosis that may ultimately lead to novel therapeutic approaches.

Public Health Relevance

Atherosclerosis is a major public health problem and leads to the highest number of mortality and morbidity in the developed world. Inflammation of the large blood vessels contributes to the development of atherosclerosis. In this proposal we will study a specific protein, HuR that binds to mRNAs involved in the inflammatory process of macrophages and endothelial cells. We will study the development of vascular inflammation and atherosclerosis in the mice that lack HuR in macrophages and endothelial cells. Our studies will attempt to uncover new mechanisms of gene regulation in inflammation and atherosclerosis. As such, this work may lead to better understanding of atherosclerosis and may yield new approaches in the treatment of heart disease and stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049094-18
Application #
8257558
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Sopko, George
Project Start
1993-09-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
18
Fiscal Year
2012
Total Cost
$418,275
Indirect Cost
$170,775
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Giammanco, Antonina; Blanc, Valerie; Montenegro, Grace et al. (2014) Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development. Cancer Res 74:5322-35
Li, Xi; Lu, Yi-Chien; Dai, Kezhi et al. (2014) Elavl1a regulates zebrafish erythropoiesis via posttranscriptional control of gata1. Blood 123:1384-92
Lu, Yi-Chien; Chang, Sung-Hee; Hafner, Markus et al. (2014) ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages. Cell Rep 9:2330-43
Chang, Sung-Hee; Lu, Yi-Chien; Li, Xi et al. (2013) Antagonistic function of the RNA-binding protein HuR and miR-200b in post-transcriptional regulation of vascular endothelial growth factor-A expression and angiogenesis. J Biol Chem 288:4908-21
Chang, Sung-Hee; Hla, Timothy (2011) Gene regulation by RNA binding proteins and microRNAs in angiogenesis. Trends Mol Med 17:650-8
Skoura, Athanasia; Hla, Timothy (2009) Regulation of vascular physiology and pathology by the S1P2 receptor subtype. Cardiovasc Res 82:221-8
Ghosh, Mallika; Aguila, Hector Leonardo; Michaud, Jason et al. (2009) Essential role of the RNA-binding protein HuR in progenitor cell survival in mice. J Clin Invest 119:3530-43
Ghosh, Mallika; Wang, Haibin; Ai, Youxi et al. (2007) COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation. J Exp Med 204:2053-61
Hla, Timothy; Feinmark, Steven J (2007) A festschrift for J. Martyn Bailey, a biochemist extraordinaire. Prostaglandins Other Lipid Mediat 83:154-7
Subbaramaiah, Kotha; Howe, Louise R; Port, Elisa R et al. (2006) HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res 66:5504-11

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