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Paul E. DiCorleto, Ph.D.Staff, Institute Chairman Lerner Research Institute / NB21 |
Area of general research interest:
Vascular Endothelial Cell Gene Expression and Atherosclerosis
Current program:
- Regulation of Endothelial Cell Gene Expression
- TNF-a Signaling through TNF receptor 2 in Endothelial Cells.
- Role of Homeobox Gene HOXA9 in Endothelial Cell Activation.
- MAP Kinase Phosphatase-1 in EC signaling.
Investigators:
- Smarajit Bandyopadhyay, Ph.D., Research Associate
- Unni Chandrasekharan, Ph.D., Project Scientist
- Daniel Harris, B.S., CWRU Graduate Student
- Corttrell Kinney, B.S., CWRU Graduate Student
- Angela Money, B.S., Technologist
- JianZhong Shen, Ph.D., Postdoctoral Research Fellow
Collaborators:
- Paul L. Fox, Ph.D.
- Xiaoxia Li, Ph.D.
- Vikram Kashyap, M.D.
- Mohammad Rajabi, M.D., Ph.D.
- Jonathan Smith, Ph.D.
Brief Description:
The central objective of our research is to understand the role of endothelial cell (EC) gene expression in blood vessel wall homeostasis and the genesis of vascular diseases. Our working hypothesis is that aberrant expression of embryonic or "pathological" genes in adult ECs leads to atherosclerotic plaque development and other inflammatory diseases.
We are pursuing the thrombin- and cytokine-activated intracellular signaling pathways and transcription factors responsible for induction of leukocyte adhesion to ECs in vivo and in vitro. We are currently focused on the relative importance of the two tumor necrosis factor-alpha receptors in the induction of leukocyte adhesion. Furthermore, we are testing the hypothesis that homeobox (HOX) genes, a family of master-control transcription factors, are involved in the process of cytokine-induced activation of ECs. We have discovered that the HOXA9 gene is required for cytokine-induced expression of the EC-leukocyte adhesion molecule E-selectin. We are identifying other EC genes that are regulated by HOXA9, and we are pursuing binding partners of HOXA9 in the EC nucleus.
Finally, we are characterizing regulatory pathways involved in the expression of inflammatory genes by ECs in response to the protease thrombin and the angiogenic agent vascular endothelial growth factor (VEGF). We are defining the mechanism of induction of the dual-specificity nuclear phosphatase MAP kinase phosphatase-1 (MKP-1) by thrombin and VEGF in ECs and determining MKP-1's role as an immediate early gene product in the induction of various downstream genes.
Key References:
- Shen, J and DiCorleto PE. ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor-mediated MAPK Pathways, Circ Res 2008:102:448-456.
- Kinney CM, et al. VEGF and thrombin induce MAP Kinase Phosphatase-1 through distinct signaling pathways: role for MKP-1 in endothelial cell migration. Am J Physiol 2008:294:C241-50.
- Bandyopadhyay S, et al. HOXA9 participates in the transcriptional activation of E-selectin in endothelial cells. Mol Cell Biol 2007;27:4207-16.
- Chandrasekharan UM, et al. Tumor necrosis factor α (TNF-α ) receptor-II is required for TNF-α -induced leukocyte-endothelial interaction in vivo. Blood 2007;109:1938-44.
- Chandrasekharan UM, et al. Decreased atherosclerosis in mice deficient in tumor necrosis factor-α receptor-II (p75). Arterioscler Thromb Vasc Biol 2007;27:e16-7.