Dr. Graham merges his research in cardiology and virology to study HIV-induced cardiomyopathy, an important emerging area in cardiovascular medicine.
His research in virology is concentrated on understanding the differences between viruses with divergent pathologies, including the ability to differentially induce apoptosis by a IFN a/B induced expression of TRAIL, in collaboration with Gene Shearer (NIH) and Jean-Phillipe Herbeuval (Necker Institute, France), and viruses with the ability to induce neurotoxicity in collaboration with Drs. Zink and Clements (retrovirus laboratory).
In cardiology, Dr. Graham focuses on the molecular phenotyping of transgenic rabbits over expressing alpha-myosin heavy chain, which has been shown to be cardioprotective against pacing induced heart failure. In this complex experimental model, Dr. Graham has been able to elucidate changes in the proteome caused by the transgene alone as compared to the background strain and differences between all groups under pacing induced heart failure. He has been collaborating on an investigation of the role of lipid rafts in the control of SA nodal cell function, and has developed ultra-sensitive mass-spectrometry methods to compare compositional changes in the lipid raft proteome between control and stimulated SA nodal cells.
Dr. Graham has been directly applying mass spectrometry and bioinformatics toward gaining understanding of the mechanisms involved in HIV pathogenesis in both the periphery and CNS for over a decade. It is becoming very clear that there is an integrated response to HIV infection, and that metabolism works hand in hand with both the development and response to disease. From the moment that innate immune responses begin to HIV metabolic responses are engaged, from increased demand from NADPH in response to oxidative stress, to responses kynurenine metabolites that can alter both immune function in the periphery and in the CNS work co-operatively exitotoxic mechanisms mediated by excess extracellular glutamate. In this application, we are extremely well-positioned to study the cross talk between metabolism and neuroinflammation under cART therapy, and how therapeutic approaches targeting glutamate excitotoxicity might be able to prevent both the ongoing CNS damage under cART and potentially protect against treatments intended to purge latent viral reservoirs.
In additional to very targeted hypothesis-driven studies, our group has been taking advantage of unbiased approaches to understanding disease by integrating information from many experimental sources. Our group has extensive experience in proteomics and more recently, we have extended our experience to the area of metabolomics and lipidomics. In Dr. Graham's role as the director for the School of Medicine for the Center for Resources in Integrative Biology (CRIB), we have been combining multiple data sources with MPP Pro software after careful validation through our method specific workflows. We have used these approaches to reveal new potential biomarkers of HAND as described within this application. In this application, Dr. Graham will work directly with Dr. Slusher as the co-PI of project 3, bringing experience in bioinformatics and data integration to help elucidate how antagonists of AMPA receptor and other glutaminergic pathways mediate their effects to prevent HAND in the TAT mouse model. Also as the co-PI for the BSL-3/Analytical Measures core, Dr. Graham will not only support similar measures in other projects, but will support novel methods like phosphopeptide enrichment in project 2 and metabolite and protein measures from the CSF and brain in project 1.
Center for Resources in Integrative Biology
Brown, J.M., N.J. Shaw, and D.R. Graham. "The first five years: a mixed methods study investigating reflections on working as a hospital consultant." JRSM Short Rep, 2013. 4(5): p. 2042533313476686.
Linde, M.E., et al. "The conserved set of host proteins incorporated into HIV-1 virions suggests a common egress pathway in multiple cell types." J Proteome Res, 2013. 12(5): p. 2045-54.
Nzowa, L.K., et al. "Two new tryptophan derivatives from the seed kernels of Entada rheedei: effects on cell viability and HIV infectivity." Fitoterapia, 2013. 87: p. 37-42.
Tavano, B., et al. "Ig-like transcript 7, but not bone marrow stromal cell antigen 2 (also known as HM1.24, tetherin, or CD317), modulates plasmacytoid dendritic cell function in primary human blood leukocytes." J Immunol, 2013. 190(6): p. 2622-30.
Tovar, Y.R.L.B., et al. "Adenosine Triphosphate Released from HIV-Infected Macrophages Regulates Glutamatergic Tone and Dendritic Spine Density on Neurons." J Neuroimmune Pharmacol, 2013.