|Date of birth||24/05/1982|
|Place of birth||Kolkata (India)|
Doctoral work (PhD) at Laboratory of Aging and Cognitive Diseases, European Neuroscience Institute, Goettingen, Germany. Supervisor: Dr. Andre Fischer
|2003-2005||M.Sc. Molecular Biology, International Max Planck Research School, Goettingen, Germany.|
|2000-2003||B. Sc. (Hons.) Human Biology, All India Institute of Medical Sciences (AIIMS); New Delhi, India|
TO ANALYZE THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH HDACs REGULATE NEURONAL FUNCTION DURING COGNITION AND ALZHEIMER’S DISEASE
The term epigenetics is most commonly defined as heritable changes in gene expression that cannot be explained by the DNA sequence. The two most studied epigenetic phenomena are DNA-methylation and Histone-tail modifications.
The DNA is wrapped around a complex of eight Histones (dimers of H2A, H2B, H3, H4) to form the basic unit/level of chromatin structure. The basic amino-terminal tails of histones carry diverse post- translational modifications, for example acetylation, methylation and ubiquitination, which build up discrete pattern of chemical marks recognized and bound by other proteins. This idea is often referred to as “histone code”. Lysine acetylation of H3 and most H4 sites leads to the relaxation of chromatin thereby making the DNA accessible for DNA binding proteins such as transcription factors. Histone acetylation is therefore generally considered to promote gene expression. The acetylation of histones is regulated by histone-acetyl transferases (HAT) and Histone-deacetylases (HDAC) that transfer or remove acetyl-groups on specific lysine residues on Histone-tails, respectively.
Recent studies from our group and others indicate that epigenetic mechanisms, namely the inhibition of HDACs, could reinstate learning behavior but most importantly also re-establish access to long-term memories in animal models for neurodegeneration (Fischer, 2007) (Alacorn, 2004) (Beglopoulos, 2006). Notably, inhibition of HDAC activity has also been implicated with improving cognitive function in wild type mice (Levenson, 2004).
However, to date little is known about the role of HDACs in neuronal function and learning and memory. In this proposal I plan to unravel the underlying molecular mechanisms by which epigenetic processes such as HDAC activity affect synaptic plasticity, learning and long-term memory. I am particularly interested in elucidating which of the 11 human zinc-dependent HDACs might be most important for the observed beneficial effects on neuroplasticity. I feel that my research will significantly contribute to further our understanding about the mechanisms underlying learning and memory and may eventually also help to develop therapeutic strategies to treat cognitive disorders such as Alzheimer’s disease (AD).
- Alarcon, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., and Barco, A. (2004). Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42, 947-959.
- Beglopoulos, V., and Shen, J. (2006). Regulation of CRE-dependent transcription by presenilins: prospects for therapy of Alzheimer’s disease. Trends in Pharmacological Sciences 27, 33-41.
- Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B., and Tsai, L. H. (2005). Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825-838.
- Levenson, J. M., O'Riordan, K. J., Brown, K. D., Trinh, M. A., Molfese, D. L., and Sweatt, J. D. (2004). Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279, 40545-40559.