Department of Molecular and Cell Biology

School of Natural Sciences and Mathematics

Faculty and Research

Santosh D'Mello, Ph.D.

Santosh R D'Mello
Professor
RL 1.708
972-883-2520

faculty profile

Education

B.S., University of Bombay
M.S., University of Bombay
Ph.D., University of Pittsburgh
Postdoctoral Training, Boston University Medical School
Postdoctoral Training, Institute of Neurobiology, Rome

Overview

During development of the mammalian nervous system, large numbers of neurons die by a process called apoptosis. Apoptosis serves to eliminate superfluous neurons and those making inappropriate connections. While essential for normal nervous system development, aberrant induction of apoptosis in the adult brain leads to undesirable neuronal loss, which has been found to occur in several neurodegenerative diseases and following stroke. The goal of my laboratory is to elucidate the mechanisms regulating apoptosis in neurons of the brain. Besides helping in our understanding of normal neurodevelopment, these studies will shed insight into how neurons die in neuropathological conditions.

Research Interests

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.

Publications (last 3 years only)

  1. Johnson K and D'Mello, SR. (2005) PAK-1 is necessary depolarization-mediated neuronal survival. J. Neuroscience Res.79, 809-815.
  2. Johnson K, Liu L Majdzadeh N, Chavez C, Chin PC, Morrison B, Wang L, Park J, Chugh P, ChenH-M, D’Mello SR (2005) Inhibition of neuronal apoptosis by the cyclin dependent kinase inhibitor GW8510: Identification of 3’ substituted indolones as a scaffold for the development of neuroprotective drugs. J. Neurochem. 93, 538-548.
  3. Chin PC, D'Mello SR. (2005) Brain chemotherapy from the bench to the clinic: targeting neuronal survival with small molecule inhibitors of apoptosis. Front Biosci. 10, 552-568.
  4. D'Mello SR, Chin PC. (2005) Treating neurodegenerative conditions through the understanding of neuronal apoptosis. Curr Drug Targets CNS Neurol Disord. 4, 3-23.
  5. Chin PC, Majdazeh N, D'Mello SR (2005) Neuroprotection by distinct survival factors involves the inhibition of Gsk3beta. Mol. Brain Res. 137, 193-201
  6. Liu L and D'Mello SR. (2006) Phosphorylation of IkΒ-β is necessary for neuronal survival. J. Biol. Chem.281, 1506 – 1515.
  7. Morrison BE, Majdzadeh N, Zhang X, Lyles L, Bassel-Duby R, Olson EN, D’Mello SR (2006) Neuroprotection by histone deacetylase-related protein. Mol. Cell Biol. 26, 3550-3564.
  8. Morrison BE, Majdzadeh N, D’Mello SR (2007) Histone Deaceylases: Focus on the Nervous System.  Cell Mol. Life Sci. 64, 2258-2269.
  9. Majdzadeh N, Morrison BE, D’Mello SR. (2008) Class II HDACs in the regulation of neuronal survival. Frontiers in Bioscience 13, 1072-1082  
  10. Zhang X, Jaramillo E, Wang L, D’Mello SR. Histone deacetylase-related protein inhibits AES-mediated neuronal cell death by direct interaction J. Neurosci. Res.(in press).
  11. Chen H-M, Wang L, D’Mello SR. (2008) Inhibition of ATF-3 expression by B-Raf mediates the neuroprotective action of GW5074. J. Neurochem. 105, 1300-1132.
  12. Majdzadeh N, Morrison BE, Wang L, D’Mello SR. (2008) HDAC4 inhibits cell cycle progression and protects neurons from cell death. Dev. Neurobiol. 68, 1076-1092.
  13. Zhang X, Jaramillo E, Wang L, D’Mello SR. (2008) Histone deacetylase-related protein inhibits AES-mediated neuronal cell death by direct interaction. J. Neurosci. Res. (in press).
  14. Morrison BE and D’Mello SR. (2008) Polydactyly in mice lacking HDAC9/HDRP. Experimental Biology and Medicine 233:980-988.
  15. Chen HM, Wang L, D'Mello SR. (2008) A chemical compound commonly used to inhibit PKR, {8-(imidazol-4-ylmethylene)-6H-azolidino[5,4-g] benzothiazol-7-one}, protects neurons by inhibiting cyclin-dependent kinase. Eur J Neurosci. 28:2003-2016.
  16. Balderamos M, Ankati H, Akubathini SK, Patel AV, Kamila S, Mukherjee C, Wang L, Biehl ER, D'Mello SR. (2008) Synthesis and Structure-Activity Relationship Studies of 3-Substituted Indolin-2-ones as Effective Neuroprotective Agents. Exp Biol Med 233:1395-1402.
  17. Ankanti H, Akubathini SK, Kamila S, Mukherjee C, D’Mello SR, Biehl ER. Synthesis of 3-benzylidene, 5-substituted 3-bennzylidene, 3-hetarylmethylene and 5-substituted hetarylmethylene derivatives of indolin-2-ones. Organic Chemistry Journal 2: 138-147.
  18. Pfister JA, Ma C, Morrison BE, D’Mello SR. Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLos One (In press).
  • Updated: February 6, 2006