Dr. D. Wade Gibson
Professor of Pharmacology and Molecular Sciences
Professor of Oncology
Ph.D., University of Chicago
Postgraduate research, Salk Institute, La Jolla, CA
Research Interests: Herpesvirus molecular biology; protein structure/function
Our group is studying the structure and molecular interactions of herpesvirus proteins with the objective of understanding their role during virus replication. The long term goal of the work is to uncover new targets for antiviral drug and vaccine development, and to better define the events involved in virus assembly and maturation. Our research has focused on cytomegalovirus (CMV), which has the largest genome (~230 kb) among the known herpesviruses and is an important sexually transmissible agent that can cause severe problems among individuals with suppressed (e.g., anti-cancer chemotherapy; organ transplantation) or dysfunctional (e.g., HIV-infected) immune systems. Several areas of our current research are outlined below:
1. Biochemical, enzymatic, physical, and genetic characterization of the viral maturational proteinase -- a current target for pharmaceutical development of antiviral drugs. The CMV proteinase represents a new mechanistic class of serine proteinases, is essential for virus replication, and is being pursued as a potential target for antiviral drug development. We are investigating the molecular biology of how this key enzyme functions in the virus-infected cell, and whether its precursor form may have different structural and enzymatic properties than the smaller proteolytic domain. These questions bear on understanding the biological function of this key regulatory enzyme, and maximally exploiting it as an antiviral target.
2. Molecular, physical, and biological description of CMV capsid formation. The herpes simplex virus (HSV) capsid is one of the largest structures that has been demonstrated to self-assemble. This same process has not been reproduced with cytomegalovirus -- a closely related virus containing homologs of all four HSV capsid proteins. We are interested in this difference and the implication that CMV requires additional host or viral functions to build its protein shell. The involvement or requirement for protein modification in this process is of particular interest, and the significance of several site-specific phosphorylations are being investigated.
3. Determine how incoming DNA-containing nucleocapsids are transported from the plasma membrane to the nucleus, and how progeny DNA-containing nucleocapsids are transported out of the nucleus. Once through the plasma membrane, herpesviruses appear to move in a directed way to nuclear pores and release their DNA cargo into the nucleus. A different process of crossing the nuclear membrane is used by progeny nucleocapsids as they mature into infectious particles. We are identifying and studying the viral and cellular proteins that mediate these processes, with the promise of uncovering novel targets for drugs that can interfere with virus replication at these steps.
Gibson, M.K. Neoadjuvant and Primary Chemoradiation Strategies n the Treatment of Esophageal Cancer. In: Yuh, D., editor. Vol. In Press, The Johns Hopkins Manual of Cardiothoracic Surgery; 2006.
Gibson, M.K.; Forastiere, A.A. Reassessment of the role of induction chemotherapy for head and neck cancer. Lancet Oncol. 2006 Jul;7(7):565-574.
Kleinberg, L.; Gibson, M.; Yang, S.; Forastiere, A.A.; Putnam, J.B. Primary Combined Modality Therapy for Esophageal Cancer. Oncology. 2006;20(5):505-511.
Montgomery, E.; Mamelak, A.J.; Gibson, M.; Maitra, A.; Sheikh, S.; Amr, S.S.; Yang, S.; Brock, M.; Forastiere, A.; Zhang, S.; Murphy, K.M.; Berg, K.D. Overexpression of claudin proteins in esophageal adenocarcinoma and its precursor lesions. Appl Immunohistochem Mol Morphol. 2006 Mar;14(1):24-30.
Kleinberg, L.; Gibson, M.K.; Forastiere, A.A. Chemoradiotherapy for localized esophageal cancer: regimen selection and molecular mechanisms of radiosensitization. Nature clinical practice. 2007 May;4(5):282-294.
Daniels, J.A.; Gibson, M.K.; Xu, L.; Sun, S.; Canto, M.I.; Heath, E.; Wang, J.; Brock, M.; Montgomery, E. Gastrointestinal tract epithelial changes associated with taxanes: marker of drug toxicity versus effect. Am J Surg Pathol. 2008 Mar;32(3):473-477.
Miyashita, T.; Shah, F.A.; Marti, G.; Wang, J.; Armstrong, T.; Bonde, P.; Gibson, M.K.; Yoshimura, K.; Montgomery, E.A.; Duncan, M.D.; Jaffee, E.M.; Harmon, J.W. Vaccine impedes the development of reflux-induced esophageal cancer in a surgical rat model: efficacy of the vaccine in a Pre-Barrett's esophagus setting. J Gastrointest Surg. 2008 Jan;12(1):2-7; discussion 7-9.
Burtness, B.; Gibson, M.; Egleston, B.; Mehra, R.; Thomas, L.; Sipples, R.; Quintanilla, M.; Lacy, J.; Watkins, S.; Murren, J.R.; Forastiere, A.A. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul;20(7):1242-1248.
Altiok, S.; Mezzadra, H.; Jagannath, S.; Tsottles, N.; Rudek, M.A.; Abdallah, N.; Berman, D.; Forastiere, A.; Gibson, M.K. A novel pharmacodynamic approach to assess and predict tumor response to the epidermal growth factor receptor inhibitor gefitinib in patients with esophageal cancer. Int J Oncol. 2010 Jan;36(1):19-27.