Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology
Usman Chaudhry - Xavier University of Louisiana
Co-Author(s): Hasahn Conway, Elise I. LeMelle, Tatyana T. Santoke, Tajhshea Walden, Thomas Vu, Sydnie Turner, Briana Jarrett, Kevin Lam, Moamen Ismail, Aizaz Ahmad, Harris E. McFerrin, and Partha S. Bhattacharjee, Xavier University of Louisiana Kenneth F. Swan, Inge Langohr, Cindy B. Morris, Konstantin G. Kousoulas, and Deborah E. Sullivan,Tulane University of Louisiana
Herpes simplex virus type 1 (HSV-1) infects greater than 90% of humans worldwide and during ocular infection produces inflammation and angiogenesis that can lead to blindness. In the United States, HSV infection is the leading cause of infection-induced blindness; nearly 40,000 new cases are reported and 300,000 cases are treated yearly. Cyclin-dependent kinases, mostly known for their involvement in the cell cycle and transcription, are involved in HSV transcription and replication. Cyclin-dependent kinase 9 (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 are testing the hypothesis that cyclin-dependent kinase 9 inhibitors (Flavopiridol, FP and 5,6-Dichloro-1-β-D-ribofuranosylbenzimid-azole, DRB) decrease angiogenesis and angiogenic signaling pathways up-regulated by angiogenic factors in vitro and in vivo. To date, we have demonstrated that these inhibitors decrease vascular endothelial cell (EC) migration, invasion, tubule formation in vitro and angiogenesis in chick embryo and mouse Matrigel angiogenesis models. We have determined that FP and DRB are non-toxic in mouse eyes, and both drugs decrease mouse corneal neovascularization due to HSV-1 infection to levels observed in mice treated with an anti-herpetic control drug. Additionally, FP and DRB block HSV-1 replication in culture and in the eye. At doses known to be specific for CDK9 in EC at which HSV replication is inhibited, global cellular transcription is not significantly reduced, suggesting that specific genes are targeted. Next generation RNA sequencing is currently being performed to determined which pathways are differentially regulated by treatment with FP and DRB.
Funder Acknowledgement(s): Louisiana Biomedical Research Network (LBRN)
Faculty Advisor: Harris McFerrin, firstname.lastname@example.org
Role: I was involved in cutting pockets in the cornea of mice, and applying various angiogenic factors including VEGF and FGF. I was also involved in administering these angiogenic factors for a week long four times a day every two hours. Lastly, I was involved in scoring the new blood vessel formation in the cornea. Taking care of the mice and sacrificing the mice also fell under my responsibilities.