Discipline: Biological Sciences
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)
Moamen Ismail - Xavier University of Louisiana
Co-Author(s): Hasahn Conway, Usman Chaudhry, Aizaz Ahmad, Thomas Vu, Elise LeMelle, Kevin Lam, Richard Schroeder, Nancy Pham, Phan Tram, Melissa Bratton, Madhusoodanan Mottamal, Guangdi Wang, Jayalakshmi Sridhar, and Harris E. McFerrin, Xavier University of Louisiana, New Orleans
Ocular vascular pathologies are associated with infectious agents such as herpes simplex virus type 1 (HSV-1), adenoviruses and bacteria as well as with contact lens-associated hypoxia. HSV-1 infection produces inflammation and abnormal blood vessel growth in the cornea that is the leading cause of infection-induced blindness world-wide. Cyclin-dependent kinases (CDK) are mostly known for their involvement in the cell cycle. CDK 1-4 and 6 are directly involved in cell cycle regulation. CDK5 is an essential kinase in sensory development and regulator of processes such as smooth muscle contraction, cell motility, and secretion. CDK7 and CDK9 are involved in the regulation of transcription. CDK9 and its downstream target, serine 2-phosphorylated RNA polymerase II, are essential in HSV-1 transcription and replication, however, to date there is little literature on the role of CDKs in HSV infection of the eye or on the efficacy of CDK inhibitors in preventing HSV-1-associated ocular neovascularization and its consequences. We have recently shown that the CDK9 inhibitors flavopiridol and 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole inhibit HSV-1 replication and reduce corneal neovascularization due to HSV-1 infection to the levels seen in trifluoridine-treated control mouse eyes. To identify potential therapeutics for the treatment of HSV-1-associated corneal neovascularization, we identified 5 putative CDK9 and vascular endothelial cell receptor (VEGFR) inhibitors (JS1-5) and tested these compounds in a chick embryo model system for their ability to reduce angiogenesis. Compounds JS1, JS2 and JS4 effectively inhibited angiogenesis induced by bFGF and VEGF in this system. All compounds tested inhibited CDK5, and to a greater extent, CDK9 and the VEGFR. The two most potent anti-angiogenic compounds, JS1 and JS2, were most inhibitory for CDK9 and VEGFR. Future experiments are planned to determine the CDK inhibition profile of these compounds at lower concentrations and to test their effectiveness in reducing pathological corneal neovascularization due to HSV-1 infection.
Funder Acknowledgement(s): NIH -NIGMS Grant # 8P20GM103424, NIH -NIGMS Grant # R25GM060926, NIH -NIGMS Grant # TL4GM118968,NIH -NIGMS Grant # UL1GM118967 Louisiana Cancer Research Consortium
Faculty Advisor: Harris McFerrin, email@example.com
Role: I was involved in the majority of this research. First we proved that FP does inhibit CDK which leads to the inhibition of HSV-1 ocular neovascularization. In collaboration with the Sridhar lab we were able to identify new potential inhibitors of CDK. I was also involved in preparing the drug solutions and administer the drugs. I was also involved in the double-blinded scoring process and assessment.