Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma (KS) tumors, primary effusion lymphoma (PEL), and Multicentric Castleman's disease. Although classical KS has a low prevalence rate worldwide, the more aggressive endemic KS, seen primarily in Africa, accounts for nearly half of the reported cancers in some regions and is the leading cause of cancer death in those areas. Despite being a pressing human health problem, there has been almost no attempt so far to develop protective and/ or therapeutic reagents against KSHV infection and its associated diseases. In addition, a majority of KSHV studies have been restricted to the overexpression system of the selected viral genes in the absence of viral complete genome and infection, leading to limited understanding of KSHV persistence and pathogenesis that are essential in developing safe and effective anti-viral agents and vaccines against this oncogenic pathogen. The major goal of our virology core is to provide supports and service for system to address these fundamental issues through KSHV BAC mutagenesis and primary rat mesenchymal stem cells (MSC) models. The efficient generation of mutants of KSHV using bacteria artificial chromosome (BAC) technology would significantly contribute to the understanding of viral gene functions in virus-host interaction. Furthermore, with KSHV, tumors usually develop long after the initial infection in very small percentage of infected hosts, indicating that cooperation with cellular genetic changes is required for the development of tumors. Our MSC models thus will be used to delineate viral genes and cellular pathways that mediate KSHV oncogenesis. Moreover, the mechanism by which gammaherpesviruses establish persistent infection in vivo and cause diseases is not understood. Experiments with individual viral genes in cultured cells have provided essential information about their possible function(s). While experiments in vitro may provide important clues as to their function(s), they cannot demonstrate how these genes contribute to pathogenesis in the complicated host system in vivo, because the network of indirect and multiple interactions during infection in vivo cannot be effectively defined in cell culture systems. Additionally, tumors usually develop long after the initial infection in a very small percentage of infected hosts, indicating that cooperation with cellular genetic change(s) is required for the developments of tumors. Addressing these issues requires an experimental system in which the host and viral genomes can be manipulated and infections can be performed in controlled manner. Thus, our core will provide a combination of in vitro molecular biology aspect within a virus context via KSHV BAC mutagenesis and in vivo viral pathogenesis through primary rat mesenchymal stem cells models to get better insights into the mechanisms underlying infection and associated disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA180779-02
Application #
8755903
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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