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Our laboratory is interested in elucidating the mechanisms by which cellular metabolism regulates the normal development of the nervous system and how metabolic alterations cause diseases of the nervous system.
Researchers in our laboratory are engaged in understanding the complex relationship between the important anabolic kinase mTOR and its inhibitor AMP kinase (AMPK) in glioblastoma (GBM). We are examining the mechanisms that allow co-activation of AMPK and mTOR in GBM. We use patient-derived primary GBM lines, orthotopic xenograft models in NSG mice as well as genetically engineered mouse models (GEMMs) to understand the spatiotemporal requirement of AMPK and mTOR during GBM evolution. Through metabolic, biochemical and genetic analysis of tumor tissue and cultured cells obtained from GEMMs, as well as that from orthotopic xenografts of human glioblastoma, we are identifying novel AMPK-regulated pathways. Specifically, we are investigating the nature of intracellular energy flux during proliferation and differentiation of normal neural stem/progenitor cells and glioblastoma cells. We are also performing ChIP-sequencing to find potential AMPK-regulated transcription factors that could play crucial roles in GBM survival.
Another area of research interest for our lab is to identify and examine the functions of mutations/deletions in GBM that exist as passenger mutations or accidental deletions coincident upon deletion of driver tumor suppressors. Through analysis of high throughput expression and sequencing data available in public domains, and follow-up genetic and biochemical validation experiments, we are examining potential vulnerability pathways that might uniquely exist in genetic subsets of GBM. We are examining if such mutations create specific vulnerability nodes that can be potentially exploited for novel therapeutics.
Our third area of interest is examining the fascinating possibility that neural stem cells in different areas of the brain are metabolically heterogeneous. In other words, neural stem cells have niche-specific metabolism that creates unique epigenetic landscapes, which in turn influence their susceptibility to acquiring genetic changes specific to a certain region of the brain.
Fireworks: Pediatric brain tumor cells expressing stem cell markers.
Proton spectroscopy of germinal zones of mouse brain.
Liquid chromatography/mass spectrometry of metabolites of normal and cancer cells.
Tumor xenografts using genetically engineered human glioblastoma cells to study drug efficacy.
Next generation RNA sequencing of normal and brain tumor cells.
Brain tumor stem-like cells expressing stem cell markers.
Proliferation of stem cells in the germinal zone of brain in an old mouse.
Brain tumor cells showing aberrant expression of glial and neuronal markers.
Proliferating cells in the brain of an old mouse expressing stem cell and glial markers.
Immunohistochemical staining showing high expression of active AMP kinase in a brain tumor.
293T cells expressing nuclear targeted AMPK beta1-GFP reporter construct.
Click to enlarge.
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