PhD, University of Pittsburgh
Mechanisms Regulating Apoptosis in Neurons of the Brain
Dr. D'Mello is a professor of molecular and cell biology with a joint appointment in the School of Behavioral and Brain Sciences.
Three major projects are underway in the laboratory:
Signal transduction pathways regulating neuronal survival: Our studies have identified several molecules that play a pivotal role in determining whether a neuron lives or dies. Among the molecules of current interest are the histone deacetylases (HDACs), a family of proteins originally identified on the basis of their ability to deacetylate histones but now known to act on a number of other non-histone proteins and regulate a variety of cellular processes including cell transformation, proliferation, senescence, differentiation, survival, and death. We recently discovered that two members of the HDAC family, HDRP and HDAC4, have the ability to prevent the death of neurons. Much effort is currently being spent in understanding the molecular mechanisms mediating neuroprotection by these HDACs. Development of approaches to deliver these HDACs to the brain might represent a novel therapeutic strategy to treat neurodegenerative diseases.
Discovery of neuroprotective drugs: As part of this project, we recently identified a chemical compound called GW5074 that has impressive neuroprotective properties. GW5074 prevents the loss of neurons and improves behavioral outcome in a mouse model of Huntington's disease. Current efforts are aimed at understanding the molecular mechanism by which GW5074 protects against neurodegeneration. Using microchip gene-array and biochemical approaches we have discovered that B-Raf plays an important role in GW5074-mediated neuroprotection and that a downstream effect is the inhibition of ATF-3 expression.
While neuroprotective at a rather narrow dose-range, GW5074 is neurotoxic when administered to cultured neurons or animals at high doses. We have begun to conduct a structure activity relationship analysis using GW5074 as the starting compound to identify chemical analogs that maintain neuroprotective efficacy but with minimal or no toxicity at higher doses.
The Flathead project: In 1996 we identified a novel rat neurological mutant called Flathead. Mutant mice have a small and flattened brain, display severe neurological abnormalities, and die within 4 weeks. The reduced brain size and ensuing neurological deficits are due to a massive loss of brain cells during late gestation. We discovered that the Flathead mutation is in the gene encoding Citron-K. We are currently trying to find out why the effect of Citron-K mutation affects only the brain and why the mutant mice display no brain abnormality until the later stages of gestation. Flathead is a useful model to study congenital brain defects seen in humans such as microcephaly, eplilepsy, and neurodegeneration.
Ghosh Dastidar S, Narayanan S, Stifani S, D'Mello SR. TLE1 combines with FoxG1 to promote neuronal survival. J. Biol. Chem. (in press).
Ghosh Dastidar S, Bardai F, Ma C, Price V, Rawat V, Verma P, Narayanan V, D'Mello SR. Isoform-specific toxicity of Mecp2 in postmitotic neurons: Suppression of neurotoxicity by FoxG1. J. Neurosci. (in press)
Bardai FH, D'Mello SR. (2011) Selective toxicity by HDAC3 in neurons: Regulation by Akt and GSK3b. J. Neurosci. 31:1746-51.