KSHV is one of the two known human oncogenic gammaherpesvirus which induces oncogenesis in infected susceptible cells. In the HIV positive immunocompromised patients, pleural effusion lymphoma (PELs), Kaposi's sarcoma (KS) and Multicentric Castleman's Disease (MCD) are common. The associated human malignancy is a major contributor to increased mortality in developing countries in this population of HIV positive patients. This study will explore epigenetic mechanism by which KSHV is regulated in endothelial cells and KS infected tissue. We will be collaborating with investigators in Shanghai and Northwest China Xinjiang province where KS incidence is quite high. We will focus on three major aims to explore the hypothesis that gene regulation in KSHV infected KS tissue is controlled by specific epigenetic changes that occur on the KSHV genome in the infected human endothelial spindle cells. We expect that genomic modifications are endothelial cell specific, and would provide clues as to the distinct profiles of expression in the KS tissue and infected endothelial cells. We will determine the specific markers which represent the epigenetic landscape in KS tissue by chromatin immunoprecipitation using specific antibodies to acetylation and methylation marks on histones. We will also identify the overall gene expression profiles related to LANA, Rta and CSL/RBP-Jk expression and the regulatory mechanisms at the viral and cellular level. Conditional expression as well as RNAi strategies for modulation of expression of LANA, Rta and CSL/RBP-Jk will be used as well as genetic mutations in the viral genomes to determine the control mechanisms that are utilized to drive proliferation of the infected KS cells. The expression profiles will be determined by RNA-Seq and analyzed for unique genes that are regulated in the viral infected cells. These will then be validated using real-time PCR analysis of the specific mRNA transcripts, as well as immunohistochemistry and immunofluorescence analysis in KS tissue and infected endothelial cells. These studies will further our understanding of KSHV latency mechanisms and provide insights for therapeutic potential by targeting the pathways activated in the KS disease.
KSHV is a major human pathogen. It is associated with 3 major proliferative diseases in humans including pleural effusion lymphomas. In the proposed collaborative studies we will focus on the epigenetic regulation of the KSHV genome in KS tissue and endothelial infected cells. The results would provide unique and novel clues for targeted therapeutic development for treatment of KS disease.
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