1340 JPA, Pinn Hall 5217
Charlottesville , VA 22908-0708
Cell signaling of protein kinases in development and disease
My broad research interest is the molecular and cellular basis of human disease, with a focus on aberrant signal transduction of protein kinases and phosphorylation. Protein kinases comprise one of the largest and most abundant gene families in humans. Both inherited germ-line and somatic mutations in kinase genes have been associated with many human diseases. Research in my lab is currently focused on the signaling mechanism and pathophysiologic functions of intestinal cell kinase (ICK), a ubiquitously expressed and highly conserved serine/threonine protein kinase. We are using both in vitro cell model systems and in vivo transgenic mouse models and a wide spectrum of experimental approaches in the areas of biochemistry, cell and developmental biology, and cancer biology to address the role of ICK in development, tissue injury repair and regeneration, and colon cancer/drug resistance. Project 1: Elucidate the molecular basis of the respiratory distress in human ECO Syndrome ICK is an essential gene in development. A loss-of-function mutation R272Q in human ICK gene is the causative mutation for human ECO (endocrine-cerebral-osteodysplasia) syndrome associated with developmental anomalies in multiple organ systems. A major research focus in my lab is to elucidate the cellular and molecular basis underlying the developmental defects that lead to the perinatal lethality phenotype of ECO using the Ick R272Q knock-in mouse model. Project 2: Elucidate the role of ICK in intestinal epithelial injury repair and regeneration ICK localizes specifically in the intestinal crypt where intestinal stem and progenitor cells reside. In vitro, we have demonstrated that ICK is important for intestinal epithelial cell proliferation and survival. Given that ICK expression is strongly induced in regenerating crypts following radiation injury, in collaboration with Dr. Steven Cohn?s lab at the UVA Digestive Health Research Center we are using an intestine-specific Ick knockout mouse model to examine the role of ICK in intestinal epithelial injury repair and regeneration. In collaboration with Dr. Richard Guerrant?s lab at the UVA Center for Global Health, we are also investigating the role of ICK in the maintenance of intestinal epithelial integrity in response to malnutrition and infection. Project 3: Investigate a novel ICK-GSK3 signaling mechanism in Colon Cancer and Drug Resistance A major challenge in current cancer therapy is the development of drug-resistance over time as a result of unexpected complexities in biological responses to drug treatment, such as compensatory and feed-back regulatory effects. Combinatory inhibition of multiple signaling pathways has emerged as an effective therapeutic strategy for the long-term cancer treatment. Developing novel targets toward key signaling molecules that inter-connect between synergistic or compensatory signaling cascades thus becomes essential for the combination therapy. Another major focus in the lab is to understand the biological significance of ICK over-expression in human colon cancer specimens and the oncogenic role of a newly-identified ICK-GSK3 signaling axis in CRC and rapamycin-resistance.