NCI Funded Research Portfolio - 3R01CA124332-02S1 Abstract

3R01CA124332-02S1 (R01)
Title	Regulation of KSHV infection and replication by MAPK pathways
Institution	UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT, SAN ANTONIO, TX
Principal Investigator	Shou-Jiang Gao	NCI Program Director	Peter Ogunbiyi
Cancer Activity	Comp Min Biomed Prog	Division	CRCHD
Funded Amount	$76,713	Project Dates	04/01/2007 - 01/31/2012
Fiscal Year	2008	Project Type	Grant
Research Topics (SICs) w/ Percent Relevance		Cancer Types (Disease Sites) w/ Percent Relevance
HHV8 (100.0%) Hematology (100.0%) Herpes - Other (100.0%) Herpes - Total (100.0%)		N/A
Common Scientific Outline
Exogenous Factors in the Origin and Cause of Cancer
Abstract	DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is etiologically associated with several AIDS-related malignancies including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In AIDS patients, oral KS is a common manifestation and often the first pathological symptom to appear, but KS frequently evolves into fatal stages involving visceral organs. Despite the success of HAART in some developed countries, KS remains an important disease of morbidity and mortality in US and worldwide. Understanding the mechanism of KSHV-induced pathogenesis could provide a scientific basis for developing novel preventive and therapeutic targets for KSHV-related malignancies. Current evidences indicate that KSHV lytic replication and the resulting constant new infection are important for sustaining the growth of KS tumors. Thus, it is essential to understand the molecular mechanisms and signaling pathways that regulate KSHV infection and replication. Our preliminary studies have shown that KSHV activates MEK, JNK and p38 multiple mitogen-activated protein kinase (MAPK) pathways during primary infection. Importantly, inhibitors of all three MAPK pathways reduce KSHV infectivity and the production of infectious virions during productive primary infection of primary human umbilical vein endothelial cells (HUVEC), and KSHV reactivation in latently-infected PEL cells. Based on these results, we hypothesize that multiple MAPK pathways regulate KSHV infection and replication during productive primary infection and reactivation from latency. To test this hypothesis, we will define the molecular mechanisms by which multiple MAPK pathways regulate KSHV infectivity (Aim I), KSHV lytic replication during productive primary infection (Aim II), and KSHV reactivation from latency (Aim III). The proposed study is highly significant because it will not only help understand the cellular pathways and mechanisms controlling KSHV infection and replication but also identify potential novel therapeutic targets.