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We are primarily interested in elucidating the functions of the AMPK signaling system in the nervous system. Specifically, we are interested to learn how AMPK regulates self-renewal, fate specification and differentiation of neural stem and progenitor cells (NPC) through phosphorylation and transcriptional regulation of target molecules. Through proteomic and genetic analysis of cells obtained from AMPK knockout mice, we are identifying novel AMPK substrates.
We are exploring the role of AMPK in adult neural stem cells. Using mice with targeted deletion of the AMPK subunits, we investigate the function of AMPK in self-renewal of adult neural stem cells, its importance in aging and in cell replacement after tissue damage such as traumatic brain injury or stroke.
Our research also focuses on examining the role AMPK plays in the development and treatment of brain cancers, particularly the role played by the different AMPK subunits in highly hypoxic solid tumors such as glioblastomas. Using knockout mouse models of human brain cancer, cell lines and human brain cancer tissue samples, we are identifying the expression and function of AMPK subunits in the different cell types that constitute these highly heterogeneous brain tumors. Our ultimate goal is to develop novel AMPK complex specific modulators that have the potential to inhibit tumor growth.
Our lab is also investigating the nature of intracellular energy flux during stem cell differentiation, de-differentiation and redifferentiation of mature cells. We are exploring the function of the AMPK signaling pathway in these processes.
There is wide variation in the spatial and temporal expression pattern of the AMPK subunits. Our goal is to identify developmental, epigenetic, genetic and stimulus-specific regulation of the AMPK subunits and understand the cellular basis and significance of such regulation.
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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