The PI proposes to elucidate the pharmacological and molecular mechanisms that underlie reactivation of latent HSV from trigeminal ganglia (TG). A variety of studies involving HSV DNA and the RNAs designated as latency-associated transcripts (LAT) will be done using animal models of HSV reactivation.
The specific aims are 1) to determine the relationship between specific sequence elements in the LAT promoter and the mechanisms that govern the ability to undergo in vivo adrenergic reactivation; 2) to detect and quantitate HSV transcripts in he TG from animals harboring latent viruses that exhibit different phenotypes and genotypes before and after adrenergic reactivation; and 3) to characterize the pharmacological and molecular mechanisms involved in propranolol inhibition of in vivo reactivation in animals harboring latent viruses that exhibit different phenotypes and genotypes. The methodology includes iontophoresis of epinephrine and hyperthermia to induce HSV reactivation, slit-lamp examination to detect spontaneous corneal epithelial lesions, sequence analysis of LAT regions of HSV DNA, detection of HSV DNA methylation, and RT- PCR to quantitate HSV RNAs. The long-term goal is to provide insights into HSV pathogenesis that could result in the development of therapeutic strategies to block neuronal HSV reactivation and the morbidity caused by repeated episodes of herpetic disease.
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