Zoltan A. Tokes Professor Biochemistry and Molecular Biology Keck School of Medicine USC / Norris Comprehensive Cancer Center

Education:
PhD 1970 - California Institute of Technology

Research Topics: Developmental Biology, Cell Cycle, Growth & Proliferation, Signal Transduction

Research Description

Investigations in our laboratory focus on two converging topics. First, we want to study the dynamic events which are involved in the maintenance and remodeling of three-dimensional cellular networks. Second, we want to find new methods by which to deliver biologically active compounds into specific tissue compartments to re-establish regular tissue architecture.

A gradual breakdown of tissue structures occurs during the progressive growth of cancer. Profound synaptic rearrangements take place during memory consolidation in the central nervous system, and a striking destruction of tissue architecture is observed in the brain with aging, especially in patients with AlzheimerÕs disease. Our research focuses on proteinases and their inhibitors since all of these events are influenced by their availability. Both metastatic cancer cells and invading nerve growth cones use matrix metalloproteinases, MMPs, capable of degrading tissue matrix components. We discovered that hippocampal neurons from Alzheimer patients express high amounts of inactive MMPs, and hypothesize that their activation may be blocked by excess inhibitors. Of interest is our observation that activated MMPs are capable of degrading amyloid peptides which would otherwise accumulate in the brain as insoluble deposits in the senile plaques. This finding also suggests that the activation of MMPs would result in more efficient destruction of amyloid peptides and reduce their accumulation in senile plaques. Consequently, the delivery of activating agents, or other biologically relevant compounds, to the brain may have therapeutic significance. Quantitation of MMP-produced fragments in the spinal fluid may provide diagnostic information. The possibility that measurement of MMP-produced amyloid fragments in the spinal fluid may provide diagnostic information is under investigation.

In situ hybridization with RNA-probe for MMP shows their synthesis in hippocampal neurons of AlzheimerÕs patients. Immunohistochemistry shows the accumulation of protease inhibitor, alpha-1-antichymotrypsin, in the same neurons.