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Research

Current research interests:
  • Non-coding RNA in neuronal function and dysfunction:
    • MicroRNAs are small, endogenous regulatory RNA that can control the expression of many protein coding genes.  Long non-coding RNAs are by definition longer than 200bp but do not seem to code for proteins.  Both miRNAs and lncRNAs are expressed in large numbers in the brain.  Many of our projects try to understand their role in neurons.  We have previously worked with a neuroblastoma cell line, Neuro2A, but are slowly gaining expertise in primary neuronal culture.  Recently, we have also used mice, knocking down a miRNA in a brain specific manner.  In our quest for better and tractable models, we are also exploring zebrafish.  Currently, a double transgenic fish marked with RFP and GFP for Radial Glia and Neurons respectively is being used in our lab.
    • Our main findings in this area are:
      • miR-29a/b
        • miR-29a/b (difficult to distinguish from miR-29c, but we conservatively call it miR-29a/b since we have not directly found miR-29c) are down-regulated in a cellular model of neurodegeneration due to toxic polyglutamine expression.
        • Knocking down miR-29a/b in cells (cultured in vitro) or in the mouse brain can cause apoptosis.  In the mouse brain, acute down-regulation surprisingly leads to ataxia like phenotype.
        • What are the targets of miR-29a/b?  We tested some (Bace1, Bcl2, Bax, Puma) reported in the literature and also found a novel target: VDAC1- believed to be a mitochondrial outer membrane protein.  Vdac1 has a weak binding site, but modulation of miR-29a/b produces a strong effect on VDAC1 levels.  
      • miR-34
        • miR-34 in zebrafish is present in mature oocytes and continues to be present in the fertilized embryos during early development.  That makes it a form of epigenetic inheritance??
        • Knocking down this maternally inherited miR-34 results in defective mid-brain- hind-brain boundary formation.
  • Histone variants and regulation of neural gene expression:
    • Histone Variants resemble histone proteins but are regulated differently and may play very specific roles in the chromatin. They are not to be confused with histone modifications- post-translational modifications of core histone proteins that mark active, inactive and bivalent regions differently.  The core histone proteins are synthesized during S-phase and directly involved in packaging the genomic DNA.  The expression of histone variants is not restricted to the S-phase.  They presumably have a different affinity to DNA and preference for certain sites.  They can displace the core histones and get incorporated in the chromatin.  We are particularly interested in two histone variants H3.3 and H2A.z because they are enriched in the mammalian brain.  We use mouse as a model for this work.  We have earlier shown an unusual arrangement of H2A.z modified nucleosomes in gene promoters.
  • Search for a nerve regeneration factor from Earthworm:
    • This is a recent interest in the lab.  The redworm, a type of top-dwelling earthworm- (Scientific name: E. foetida) when cut into two halves regenerates the posterior.  In spite of reports in the literature, we have never been able to get the anterior portion to regenerate.  The posterior, as it regenerates, presumably regrows the ventral nerve chord that runs along the length of its tubular body and forms connections in the newly formed tissue.  We are in the search of a nerve growth factor with novel properties from this annelid.