Research
in Dr. Aizenman’s laboratory is directed towards investigating cellular signaling processes leading to neuronal cell death.
Acute and chronic injurious processes in the brain lead to the activation of signaling cascades that eventually result in the demise of neurons. In Dr. Aizenman's laboratory, the molecular pathways leading to cell death are being carefully dissected in order to provide novel therapeutic targets to treat neurodegenerative disorders. This laboratory works on the premise that there are common final mediators of cell death signaling events that can be effectively targeted to treat neural disorders. This work if primarily focused on acute neuronal injury, such as that occurring during stroke, trauma and epilepsy. Nonetheless, the results obtained from these studies could have broader applications to more chronic conditions, such as Parkinson's and Alzheimer's disease.
Dr. Aizenman’s
laboratory has observed that oxidants can liberate zinc from metalloproteins
in neurons. Importantly, intracellular zinc release triggers caspase-dependent
and caspase- independent cell death processes. The caspase-dependent pathway requires
activation of p38 MAPK and an enhancement of voltage-gated potassium currents
encoded by Kv2.1, following the exocytotic, SNARE-dependent, membrane insertion
of these channels. This process occurs following the direct phosphorylation
of Kv2.1 by p38. Therapeutic interventions have included chelation of the zinc signal, inhibition of the p38 signaling cascade, or interference with the function of Kv2.1.
Intracellular liberation
of zinc is a critical mechanism that contributes to neurodegenerative
processes in vivo in conditions of oxidative and nitrative stress, including
exposure to certain occupational and environmental neurotoxins.
Most recent publications:
Redman, P.T.,
K. He, K.A. Hartnett, B.S. Jefferson, L. Hu, P.A. Rosenberg, E.S. Levitan
and E. Aizenman. Apoptotic surge of potassium currents is mediated by
p38 phosphorylation of Kv2.1. Proc.
Natl. Acad. Sci. (U.S.A.) 2007; 104:3568-3573.
Zhang, Y., E. Aizenman, D.B. DeFranco and P.A. Rosenberg. Intracellular zinc release,12-lipoxygenase activation and MAPK dependent neuronal and oligodendroglial death. Mol. Med. 2007; 13:350-355.
Knoch, M.E., K.A. Hartnett, H. Hara, K. Kandler and E. Aizenman. Microglia induce neurotoxicity via intraneuronal Zn(2+) release and a K(+) current surge. Glia 2008; 56:89-96.
Aras, M., K.A. Hartnett and E. Aizenman. Assessment of cell viability in primary neuronal cultures. Current Protocols in Neuroscience 2008; Suppl. 44: 7.18.1-7.1815.
Ho Y., R. Samarasinghe, M.E. Knoch, M. Lewis, E. Aizenman and D.B. DeFranco. Selective inhibition of MAPK phosphatases by zinc accounts for ERK1/2-dependent oxidative neuronal cell death. Mol. Pharmacol. 2008 (in press).
|
