31-353 Lineberger Comprehensive Cancer Center, CB #7295
The work in our laboratory is focused on understanding the molecular pathogenesis of Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV is associated with a number of human malignancies including Kaposi's sarcoma (KS) and lymphoproliferative diseases such as body cavity-based lymphomas, primary effusion lymphomas, and multicentric Castleman's disease. Malignancies associated with KSHV are usually (but not always) seen in the context of immune-suppression i.e. in HIV-infected individuals and transplant patients. KSHV belongs to the gamma-2 (rhadinovirus) grouping of herpesviruses. Herpesviruses are characterized by their ability to persist in either a latent or lytic phase in the host. In latent infection, viral gene expression is limited and the viral genome remains associated with the cell for many generations without virus production. However, during the lytic phase there is a temporal order of viral gene expression resulting in the production of infectious viral progeny. The mechanism by which KSHV induces cellular transformation is currently unknown and our lab is focused on understanding how the virus transforms cells and persists in them. We also study basic cellular and viral mechanisms that determine how KSHV is able to maintain the latent and lytic phases of its lifecycle. Specific projects are listed as follows:
- We study KSHV viral proteins that are involved in cellular transformation and modulation of cell signaling pathways. These studies involve investigating the effect of viral proteins on cell proliferation, apoptosis and cell signal transduction pathways.
- Kaposi’s sarcoma is a highly angiogenic tumor and we are currently investigating how viral proteins encoded by KSHV are responsible for the induction of angiogenesis.
- Our lab studies viral transcription factors and how they help the virus to replicate and persist in the host cell.
- We are developing therapeutics that curb viral replication and prevent virus persistence that will allow us to translate basic research into clinical application.
- We also study host-pathogen interactions, specifically we are looking at how KSHV interacts with the innate immune system
- In addition, we work on the simian homologue of KSHV named rhesus monkey rhadinovirus (RRV). RRV shows high sequence-relatedness to KSHV but unlike its human counterpart can be grown lytically and to high titers in cell culture. This facilitates the making of recombinant viruses that allow us to study the properties of a number of viral genes in the lifecycle of the virus. We use RRV as animal model system to understand KSHV pathogenesis in vivo and in vitro.
- We have recently developed the UNC Global Oncology program. This program's goal is to address disparities in cancer incidence and death across the globe. The program's mission currently includes clinical sites in the United States, Brazil, Malawi, India, and China. Please visit the following website for more information: http://www.unclineberger.org/global
In summary, our lab is interested in the study of viral oncogenes and viral transcription factors of KSHV, host-pathogen interactions, innate immunity, and using RRV as an animal model system to study KSHV pathogenesis. The projects in our laboratory encompass the areas of signal transduction, apoptosis, angiogenesis, innate immunity, transcription and recombinant herpesvirus production. We employ the latest techniques in molecular biology, cell biology and biochemistry to investigate key issues in viral oncogenesis.
Bhatt, AP., Jacobs, SR., Freemerman, AJ, Makowski L, Rathmell, JC, Dittmer, DP, and B. Damania. Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma. 2012. Proceedings of the National Academy of Sciences (PNAS). Jul 17;109(29):11818-23.
Lei Y, Wen H, Yu Y, Taxman DJ, Zhang L, Widman DG, Swanson KV, Wen KW, Damania B, Moore CB, Giguère PM, Siderovski DP, Hiscott J, Razani B, Semenkovich CF, Chen X, Ting JP. The Mitochondrial Proteins NLRX1 and TUFM Form a Complex that Regulates Type I Interferon and Autophagy.Immunity. 2012. 36(6):933-46.
Gregory SM, Wang L, West JA, Dittmer DP, Damania B. Latent Kaposi's sarcoma-associated herpesvirus infection of monocytes downregulates expression of adaptive immune response costimulatory receptors and proinflammatory cytokines. J Virol. 2012 Apr;86(7):3916-23. Epub 2012 Jan 25.
Guilluy C, Zhang Z, Bhende PM, Sharek L, Wang L, Burridge K, Damania B. Latent KSHV infection increases the vascular permeability of human endothelial cells. Blood. 2011 Aug 31.
Roy D, Sin SH, Damania B, Dittmer DP. Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines. Blood. 2011 Aug 18;118(7):e32-9.
Gregory,SM, Davis,BK., West, JA., Taxman, D., Matsuzawa, S., Reed, J., Ting. JP, and B. Damania. Discovery of a Viral NLR Homolog that Inhibits the Inflammasome. Science. 2011.
Ozgur S, Damania B, Griffith J. The Kaposi's sarcoma-associated herpesvirus ORF6 DNA binding protein forms long DNA-free helical protein filaments. J Struct Biol. 2011
West JA, Gregory SM, Sivaraman V, Su L, Damania B. Activation of Plasmacytoid Dendritic Cells by Kaposi's Sarcoma-Associated Herpesvirus. J Virol. 2011. 85(2):895-904.
Bhende PM, Park SI, Lim MS, Dittmer DP, Damania B. The dual PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular lymphoma. Leukemia. 2010. 24(10):1781-4.
Bhatt, AP, Bhende, PM, Sin, SH, Roy, D, Dittmer, DP and B. Damania. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010. 115(22):4455-63.
Wen, K and B. Damania. HSP90 and HSP40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1. Oncogene. 2010. 29(24):3532-44.
González CM, Wang L, Damania B. KSHV Encodes a Viral Deubiquitinase. J Virol. 2009 Oct;83(19):10224-33.
Wen, KW, Dittmer, DP and B. Damania. Disruption of LANA in rhesus rhadinovirus generates a highly lytic recombinant virus. J Virol. 2009 Oct;83(19):9786-802.
Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. Toll-like receptor signaling controls reactivation of KSHV from latency. Proc Natl Acad Sci U S A. 2009 Jun 29.
O'Hara AJ, Chugh P, Wang L, Netto EM, Luz E, Harrington WJ, Dezube BJ, Damania B, Dittmer DP. Pre-micro RNA signatures delineate stages of endothelial cell transformation in Kaposi sarcoma. PLoS Pathog. 2009 Apr;5(4).
O'Hara AJ, Wang L, Dezube BJ, Harrington WJ Jr, Damania B, Dittmer DP. Tumor suppressor micro RNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma. Blood. 2009 Feb 27.
Wang, L. and B. Damania. KSHV confers a cell survival advantage to endothelial cells. Cancer Research. 2008. 68(12):4640-8.
Tomlinson, CC and B. Damania.A critical role for endocytosis in the regulation of signaling by the KSHV K1 protein. J. Virology. 2008. 82(13):6514-23.
West, J. and B. Damania. Upregulation of the TLR3 pathway by Kaposi's sarcoma-associated herpesvirus during primary infection. J. Virology. 2008. 82(11):5440-9.
The principal investigator, Dr. Blossom Damania, has been the recipient of the following:
- V Foundation Scholar Award (2001)
- American Herpes Foundation Research Scholar Award (2003)
- AACR-Gertrude Elion Scholar Award (2004)
- Leukemia & Lymphoma Society Scholar (2005-2010)
- Jefferson-Pilot Junior Faculty Award in Academic Medicine (2005)
- American Heart Established Investigator Award (2006-2011)
- Burroughs-Wellcome Fund Investigator in Pathogenesies of Infectious Disease (2006-2011)
- Ruth and Phillip Hettleman Prize for Artistic and Scholarly Achievement, 2008.
- Dolph O. Adams Award, Society for Leukocyte Biology, 2011.
- Kavli Fellow, National Academy of Sciences, USA. 2011.
Recent accomplishments of our lab include the following:
- We have demonstrated that the KSHV K1 transforming protein can activate the PI3K/Akt signaling pathway in B cells resulting in protection of these cells from Fas-mediated apoptosis.
- We have found that in endothelial cells, the K1 protein is capable of upregulating expression and secretion of an essential angiogenic factor, VEGF, as well as the invasion factor, MMP-9.
- We have identified a 125 bp promoter element which regulates expression of the KSHV K1 gene.
- We have developed protocols to use rhesus monkey rhadinovirus (RRV) as a tractable system to study KSHV. RRV is the rhesus homolog of KSHV and provides us with an attractive animal model system. We have developed a system to make recombinant RRV viruses and have made the first recombinant RRV virus that expresses GFP protein.