The Zika ThreatASM Acts to Counter Zika Virus Outbreak.
There are two principal areas of research in Dr. Silverman’s laboratory. The first concerns antiviral innate immunity mediated by interferons (IFN). RNase L is a principal effector of the IFN-inducible antiviral response and is thus critically important for human health. Viral replication in higher vertebrates is restrained by IFNs. IFNs cause cells to transcribe genes for antiviral proteins, including the 2',5'-oligoadenylate synthetases (OAS). The viral pathogen associated molecular pattern (PAMP), double-stranded RNA, activates OAS. OAS produces 2’,5’-oligo(rA) whose function is to stimulate RNase L. The OAS-RNase L system constitutes a classical innate immune pathway that rapidly responds to PAMPs to produce a broadly active antiviral response. In prior studies, he cloned RNase L, knocked it out in mice, established its antiviral and apoptotic activities in vivo, and determined that it initiates transcriptional signaling pathways. In a recent development, he has found that RNase L cleaves viral RNA as well as self-RNA to generate small RNA products that stimulate IFN-beta synthesis through the RNA recognition receptors, RIG-I and MDA5, and their adapter IPS-1/MAVS.
The second area of research concerns the role of viruses and genetics in prostate cancer. Prostate cancer is the leading cause of non-cutaneous malignancies and the second leading cause of cancer-related deaths among American men. Hereditary prostate cancer (HPC), which accounts for 43% of early onset cases and about 9% of all cases, is due to germline mutations in HPC genes. HPC1 encodes RNase L thus implicating an antiviral pathway in tumor suppression. Dr. Silverman’s hypothesis is that RNase L suppresses prostate cancer by restricting oncogenic viruses and by stimulating apoptosis. His laboratory’s future goals are to probe fundamental events and biologic endpoints surrounding RNase L that impact on viral replication cycles and tumor biology.