Basic Research:

I am interested in new treatments strategies for ischemic stroke and am particularly interested in endogenous neuroprotective pathways which may make neurons more tolerant to the stresses of ischemia. Of these pathways, the induction of the heat shock proteins (HSPs) is the most ubiquitous and the most evolutionarily conserved. As such, HSPs have been widely studied in neuroprotection.

Our lab has been studying a key modulator of HSPs, the co-chaperone CHIP (carboxyl terminus of HSC70-interacting protein). CHIP is a chaperone-dependent ubiquitin ligase that works with HSPs to add ubiquitin to target proteins, which leads to proteasomal degradation of the modified proteins. Recent observations strongly support a cytoprotective role for CHIP. Mice lacking CHIP were extremely sensitive to heat stress.

In the nervous system, CHIP was recently identified as a potential neuroprotective protein in neurodegenerative diseases. In preliminary studies, we have shown that CHIP is highly expressed in neurons. In our biochemical studies, CHIP translocated from the cytoplasm into the nucleus following heat stress, and the time course for the translocation was similar to that for nuclear increase of heat shock cognate 70 (HSC70). Since CHIP and HSC70 show similar patterns of trafficking, we suspect that nuclear CHIP/HSC70 complexes modify specific nuclear targets via ubiquitination. In support of such a notion, we have demonstrated that a number of ubiquitinated proteins were bound to nuclear CHIP, and, for a few of these proteins, the amount increased following heat stress.

The general hypothesis being tested in my current research is that CHIP is neuroprotective following cerebral ischemia. We are currently utilizing a dissociated cortical culture model of ischemia to further clarify the biochemical properties of CHIP during ischemia. We will also be utilizing mouse models of stroke to study the effects of cerebral ischemia in CHIP (-/-) and wild-type mice.

Clinical Research:

As the Associate Director of the UNC Stroke Center, I am involved in numerous clinical studies and trials. I also assist Dr. Sen (Director of the Center) in overseeing the entire study effort of our clinical trials unit.