Infection can initiate and accelerate atherogenesis leading to overt clinical ischemic events. Human cytomegalovirus (HCMV) as one of the commonest infectious agents in adult population is associated with atherosclerotic diseases. HCMV can specifically invade endothelial cells to establish latency for a life-long presence. When reactivated under compromised host defense conditions, HCMV can result in acute and chronic endothelial injury hence vascular disease. However, molecular mechanism for HCMV induced endothelial injury is not clear. We have designed present study to systemically explore expressional changes in endothelial cells and vascular smooth muscle cells infected with HCMV which could be relevant to atherogenesis. To explore the signal transduction pathways involved in dysregulated endothelial apoptosis after HCMV infection, we will test both p53-dependent and -independent apoptotic pathways for their relevance. We hypothesize that p53 is the primary molecular target by HCMV, in which p53 inactivation after HCMV infection facilitate HCMV propagation and infection as well as other dysfunctional changes. We and others have found that HCMV inactivate p53 by displacing the p53 protein to either viral replication center within the nucleus or in cytoplasm. We suggest that the p53 inactivation is mediated by a direct binding between HCMV protein(s) and p53. In this study, we will identify HCMV protein(s) that are capable of sequestering p53 at dysfunctional sites using a recombinant vector containing p53 nuclear localization signals to separate the protein(s) from the cytoplasm of HCMV infected endothelial cells. The protein(s) will be sequenced before further functional analysis in vivo. This project will not only provide more understanding for HCMV related atherogenesis, it will also open up potential pathways to inhibit or even to reverse HCMV induced endothelial dysfunction. The findings of the study can also be applicable to other virus-related pathogenesis, such as cancer. The present study can potentially lead us to a larger project in exploring drugs that can treat chronic disorders associated with HCMV infection, hence consequential pathological changes.
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