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Cheikh Seye, Ph.D.

Assistant Professor

Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, Room 332
Indianapolis, Indiana 46202-5120

E-mail: cseye @ iupui.edu
Phone: 317-274-8528
Facsimile: 317-274-3318

Education / Training

  • 1998, M.S. in Cell & Molecular Biology, University of Paris 7, France
  • 2000, Ph.D. in Cell & Molecular Biology, University of Paris 7, France
  • 2000, Postdoctoral Fellowship, University of Antwerp, Belgium
  • 2000-2002, Postdoctoral fellowship, University of Missouri-Columbia

Research Biography Summary

Personal Statement

   My research is centered on the pathophysiology of atherosclerosis, a disease that will likely remain a global health problem for the next several decades. My laboratory is interested in identifying new molecular pathways that may be targeted to prevent or control the progression of the disease. My enthusiasm in this research topic stems from my early interest in understanding the mechanisms of coronary artery disease as a PhD student. I cloned one of the first mammalian nucleotide receptors, the P2Y2 nucleotide receptor (P2Y2R) that binds Adenosine 5’-triphosphate (ATP), a crucial signaling molecule implicated in many physiological functions in humans. The critical observation that forms the central hypothesis of my work is that under patho-physiological conditions, nucleotide release from blood-derived and vascular cells activates P2Y2 receptors leading to arterial recruitment of leukocytes and intimal accumulation of vascular smooth muscle cells (SMC), two key events in the pathogenesis of atherosclerosis. The significance of my work is evidenced by the growing number of purinergic antithrombotic drugs that significantly reduce the risks of recurrent strokes and heart attacks. These drugs are antagonists to the P2Y12 receptor that mediates platelet aggregation. However, the current scarcity of receptor subtype specific agonists and antagonists that are stable and effective in vivo limits the availability of more purinergic therapies. Therefore my research has clear goal of obtaining mechanistic insights into how P2Y2R coordinate the progression of atherosclerosis. In the past few years, I developed new and unique innovative tools to achieve my research goals. This include the generation of new mouse models to study the role of P2Y2R in the atherosclerotic process. In particular, I generated apolipoprotein E-knockout (ApoE KO) mice with deletion of the P2Y2R gene to study the overall contribution of P2Y2R to the development of atherosclerosis. In addition, I also generated mice with cell-specific deletion of P2Y2R either in endothelial cell or smooth muscle cells. These tools have enabled us to begin addressing the relative contribution of endothelial versus smooth muscle cell P2Y2R to development of atherosclerosis in the ApoE KO mouse model of the disease. I anticipate that a detailed understanding of the function of this receptor in blood-derived and vascular cells will lead to the discovery of new anti-inflammatory targets for the treatment or prevention of atherosclerosis.

 Contribution to science

*In my earlier work (PhD training) I cloned one of the first mammalian receptors to adenosine 5’-triphosphate (ATP), the P2Y2 nucleotide receptor (P2Y2R) formerly known as P2U. I also demonstrated that P2Y2R was associated with the development of intimal lesions characteristic of atherosclerosis and postangioplasty restenosis.

  • Malam-Souley R, Seye Cl, Gradeau AP, Loirand G, Pilois X, Campan M, Pacaud P, Desgranges, C. Nucleotide Receptor P2u Partially Mediates ATP-induced Cell Cycle Progression of Aortic Smooth Muscle Cells.  1996. J Cellular Physiology.
  • Seye CI, Gadeau AP, Daret D, Dupuch F, Alzieu P, Capron L, Desgranges C. Overexpression of the P2Y2 purinoceptor in Intimal lesions of the Rat Aorta. 1997. Arterioscler Thromb Vasc Biol. 17:3602-3610.

 *As a postodoctoral fellow, I showed that during endothelial dysfunction, nucleotide release from blood-derived and vascular cells activates P2Y2 receptors leading to endothelial recruitment of leukocytes and intimal accumulation of vascular smooth muscle cells. I also demonstrated that activation of the P2Y2R regulates VCAM-1 expression. These seminal studies opened a new area of investigation in the purinergic receptor field.

  • Seye CI, Kong Q, Erb L, Garrad RC, Krugh, B, Wang M, Turner JT, Sturek M, González FA, Weisman GA. Functional P2Y2 Nucleotide Receptors Mediate UTP- induced Intimal Hyperplasia In Collared Rabbit Carotid Arteries. 2002. Circulation. 106:2720-2726.
  • Seye CI, Yu N, Jain R, Kong Q, Tess M, Newton J, Erb L, Gonzalez F, Weisman G. The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells. 2004. J Biol Chem. 278279:24960-24965.

 

*Another important contribution to the field is the finding that P2Y2R interacts directly with growth factor receptors to transactivate their signal transduction pathways. For example, we have shown the importance of P2Y2R interaction with vascular endothelial cell growth factor receptor (VEGFR1) in the regulation of VCAM-1 expression.

  • Seye CI, Yu N, Gonzalez F, Erb L, Weisman G. The P2Y2 Nucleotide Receptor Mediates Vascular Cell Adhesion Molecule-1 Expression through Interaction with VEGF Receptor-2 (KDR/Flk-1). 2004. J Biol Chem. 279:35679-35686.
  • Liu J, Griffin K, Santiago-Pérez LI, González FA., Seye CI, Weisman GA, Erb L. Src Homology 3 Binding Sites in the P2Y2 Nucleotide Receptor Interact with Src and Regulate Activities of Src, Proline-rich Tyrosine Kinase 2, and Growth Factor Receptors. 2004. J Biol Chem 279:8212-8218.

 

*Activation of the P2Y2R causes dynamic reorganization of the actin cytoskeleton, which transmits biochemical signals and forces necessary for cell locomotion, suggesting that P2Y2Rs may be linked to the actin cytoskeleton. My research identified filamin A (FLNa) as a P2Y2R-interacting protein. We characterized the interaction between FLNa and the P2Y2R in biochemical assays and used wild-type (WT) and P2Y2R knockout (KO) mice to show that the loss of this interaction affects spreading and migration of aortic SMC.

  • Liao Z, Seye, CI, Weisman GA, Erb, L. The P2Y2 Nucleotide Receptor Requires Interaction with alphav Integrins to Access and Activate G12. 2007. J Cell Sci. 120:1654-1662.
  • Yu N, Erb L, Shivaji R, Weisman G, Seye, CI. Binding of the P2Y2 Nucleotide Receptor to Filamin A Mediates Migration of Vascular Smooth Muscle Cells. 2008. Circ Res. 102:581-588.

 

*Targeted control of pro-inflammatory factors that have the potential to support endothelial dysfunction could have a significant impact on the limitation of vascular complications. Our studies have uncovered a new pathway whereby P2Y2R activation induces the secretion of lymphotoxin-alpha (LT-α), a major cytokine implicated in the development of atherosclerosis. In collaboration with Dr. Carl Ware (Sanborn institute, CA), we explored the ability of lymphotoxin-alpha neutralizing antibodies to reduce vascular inflammation and retard the progression of atherosclerosis. We demonstrated its efficacy in preventing early atherosclerotic lesion formation.

  • Seye, CI, Agca Y, Agca C, Derbigny W. P2Y2 Receptor-mediated lymphotoxin-α secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells. 2012. J Biol Chem. 287:10535-10543.
  • Shaomin Qian; April Hoggatt; Yava L. Jones-Hall; Carl F. Ware; Paul Herring; Cheikh I. Seye.. Deletion of P2Y2 Receptor Reveals a Role for Lymphotoxin-α in Fatty Streak Formation. 2016. Vascular Pharmacology. doi: 10.1016/j.vph.2016.06.001. 

 

*We have recently demonstrated that P2Y2R mediates low density lipoprotein uptake by vascular SMC, further supporting the role of this receptor in the physiopathology of atherosclerosis.

  • Tixieanna Dissmore; Cheikh Seye*; Denis Medeiros; Gary Weisman; Barry Bradford. The P2Y2 Receptor Mediates Uptake of Matrix-retained and Aggregated Low Density Lipoprotein in Primary Vascular Smooth Muscle Cells. 2016, doi: 10.1016/j.atherosclerosis.2016.07.927.

B.      RESEARCH SUPPORT

GRANT SUPPORT

National Institutes of health: R01 HL112883. Exploring the Contribution of a Nucleotide Receptor to Atherosclerosis. Dates: 07/01/2013-06/30/2018.  Principal Investigator.

 

SELECTED PUBLICATIONS

  1. Shaomin Qian; April Hoggatt; Yava L. Jones-Hall; Carl F. Ware; Paul Herring; Cheikh I Seye.

Deletion of P2Y2 Receptor Reveals a Role for Lymphotoxin-α in Fatty Streak Formation. 2016.

Vascular Pharmacology. 2016, doi: 10.1016/j.vph.2016.06.001. 

  1. Tixieanna Dissmore; Seye C; Medeiros D; Weisman G; Bradford B, Mamedova L. The P2Y2 Receptor Mediates Uptake of Matrix-retained and Aggregated Low Density Lipoprotein in Primary Vascular Smooth Muscle Cells. 2016. doi: 10.1016/j.atherosclerosis.2016.07.927.
  2. Yuksel Agca, Shaomin Qian, Cansu Agca and Cheikh I Seye. Direct Evidence for P2Y2 Receptor      Involvement in Vascular Response to Injury. 2016. Journal of vascular Research. In press.
  3. Seye CI, Agca Y, Agca C, Derbigny W. P2Y2 Receptor-mediated lymphotoxin-α secretion Regulates Intercellular Cell Adhesion Molecule-1 Expression in Vascular Smooth Muscle Cells. 2012. J Biol Chem. 287:10535-10543.
  4. Peterson TS, Camden JM, Wang Y, Seye CI, Wood WG, Sun GY, Erb L, Petris MJ, Weisman GA. P2Y2 Nucleotide Receptor-mediated Responses in Brain Cells. 2010. Mol Neurobiol. 41:356-366.
  5. Baker OJ, Schulz DJ, Camden JM, Liao Z, Peterson TS, Seye CI, Petris MJ, Weisman GA. Rat Parotid Gland Cell Differentiation in Three-dimensional Culture.  2010. Tissue Eng. 16:1135-1144.
  6. Ratchford AM, Baker OJ, Camden JM, Rikka S, Petris MJ, Seye CI, Erb L, Weisman GA. P2Y2 Nucleotide Receptors Mediate Metalloprotease-dependent Phosphorylation of EGFR and ErbB3 in Human Salivary Gland Cells. 2010. J Biol Chem. 285:7545-7555.
  7. Kong Q, Peterson TS, Baker O, Stanley E, Camden J, Seye CI, Erb L, Simonyi A, Wood WG, Sun GY, Weisman GA. Interleukin-1beta Enhances Nucleotide-induced and a-secretase-dependent Amyloid Precursor Protein Processing in Rat Primary Cortical Neurons via Up-regulation of the P2Y2 Receptor. 2009. J Neurochem. 109:1300-1310.
  8. Agca C, Seye Cl, Shivaji R, Weisman G, Chan A, Agca Y. Development of a Novel Transgenic Rat Overexpressing the P2Y2 Nucleotide Receptor Using a Lentiviral Vector. 2009. J Vasc Res. 46:447-458.
  9. Yu N, Erb L, Shivaji R, Weisman G, Seye, CI. Binding of the P2Y2 Nucleotide Receptor to Filamin A Mediates Migration of Vascular Smooth Muscle Cells. 2008. Circ Res. 102:581-588.
  10. Shen J, Seye Cl, Wang M, Weisman GA, Wilden PA, Sturek M. Cloning, Up-regulation, and Mitogenic Role of Porcine P2Y2 Receptor in Coronary Artery Smooth Muscle Cells. 2004. J Mol Pharmacol. 66:1265-1274.
  11. Seye CI, Knaapen MWM, Daret D, Desgranges C, Herman AG, Kockx MM. 7-Ketocholesterol Induces Reversible Cytochrome C Release in Smooth Muscle Cells in Absence of Mitochondrial Swelling. 2004. J Cardiovasc Res. 64:144-153.
  12. Seye CI, Yu N, Gonzalez F, Erb L, Weisman G. The P2Y2 Nucleotide Receptor Mediates Vascular Cell Adhesion Molecule-1 Expression through Interaction with VEGF Receptor-2 (KDR/Flk-1). 2004. J Biol Chem. 279:35679-35686.
  13.  Seye CI, Yu N, Jain R, Kong Q, Tess M, Newton J, Erb L, Gonzalez F, Weisman G. The P2Y2 Nucleotide Receptor Mediates UTP-induced Vascular Cell Adhesion Molecule-1 Expression in Coronary Artery Endothelial Cells. 2003. J Biol Chem. 278:24960-24965.
  14. Seye Cl, Kong Q, Erb L, Garrad RC, Krugh, B, Wang M, Turner JT, Sturek M, González FA, Weisman GA. Functional P2Y2 Nucleotide Receptors Mediate UTP- induced Intimal Hyperplasia In Collared Rabbit Carotid Arteries. 2002. Circulation. 106:2720-2726.

 

Updated: 08/2016

635 Barnhill Drive, Medical Science Bldg. Room 385 | Indianapolis, IN 46202-5120 | 317-274-7772