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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.
A neurosphere cultured from mouse embryonic forebrain.
Nestin (green) expressing neural progenitor cells differentiating into O4 (red) expressing oligodendrocytes.
Embryonic neurons differentiating from neurospheres expressing TuJ1 (red) and Map2 (green).
Embryonic astrocytes expressing GFAP (green) and oligodendrocytes expressing O4 (red) differentiating from neurospheres.
Neurospheres from the AMPK beta1 knockout mouse exhibiting apoptosis in culture (red; propidium iodide).
Gene trap construct used to make the AMPK beta1 knockout mouse.
293T cells expressing nuclear targeted AMPK beta1-GFP reporter construct.
Two-week-old sick AMPK beta1 knockout mouse (left) and healthy wild-type littermate (right).
Proliferating cells detected in the AMPK beta1 knockout embryonic brain using the Ki67 antibody (red) and BrdU antibody (green).
Apoptosis (cleaved caspase 3, red) of embryonic neurons (TuJ1, green) in the developing brain of the AMPK beta1 knockout mouse.
Mitotic cells detected in the AMPK beta1 knockout embryonic brain using the phosphohistone H3 antibody (red) and BrdU antibody (green).
Histology of AMPK beta1 knockout embryonic cerebellum showing degeneration of granule cell neurons.
AMPK beta1 embryonic forebrain showing proliferating cells (BrdU, green) and apoptotic cells (cleaved caspase 3, red).
Human brain cancer cells in mitosis expressing active AMPK (orange); chromosomes are in blue.
Presence of active AMPK (brown staining) in high-grade brain tumor; blue stain marks all nuclei.
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