Grants and Contracts per year
Grants and Contracts Details
Brain metabolism is the biochemical foundation of cognition, memory, and behavior. Glucose is both the spark and the fuel igniting the complex and intertwined brain metabolome. The brain accounts for 60% of total glucose utilization in the resting state. Defects in glucose metabolism are an emerging hallmark of multiple neurological diseases including: Alzheimer’s disease (AD), brain-centric glycogen storage diseases (GSDs), refractory epilepsy, amyotrophic lateral sclerosis (ALS), and aging. Strikingly, defects in brain glucose metabolism have received little attention. A unifying hallmark of these neurological diseases is the accumulation of aberrant, intracellular glycogen-like aggregates known as polyglucosan bodies (PGBs). The disease where glycogen metabolism and PGBs have been investigated in-depth is Lafora disease (LD). LD is an autosomal recessive, fatal epilepsy that equally affects both sexes. Symptoms emerge in adolescence with myoclonic epilepsy, ataxia and dementia, rapid neurodegeneration, and a vegetative state before death often within 10 years of onset. In LD patients and mouse models, PGBs are observed in the cytoplasm of cells from nearly all tissues, including astrocytes and neurons. Importantly, multiple labs have demonstrated that PGBs are the etiological agent driving LD. The Gentry lab has made foundational discoveries regarding aberrant glucose metabolism in LD while developing multiple cutting-edge tools to determine the underlying cellular mechanisms and developing a therapeutic platform. These insights and tools allow us to now define the role of PGBs in brain-centric GSDs and AD. Our work is currently supported by a R01 and P01. I am director for the P01 entitled Lafora Epilepsy: Basic mechanisms to therapy that unites leading LD labs. This R35 would integrate our LD efforts into one grant and allow us to apply our expertise to neurological GSDs and AD while exploring PGBs in ALS and refractory epilepsy. Moving forward, we will define LD-driven perturbations in signaling at the molecular level, elucidate changes in cellular physiology, and establish novel therapeutic modalities at the organismal level. We will apply the LD tools and insights to define how PGBs impact multiple neurological diseases, determine the glycogen-centric molecular mechanisms impacting disease progression, and define how PGB removal effects brain metabolism as a pre-clinical therapeutic. Importantly, we have key pieces of preliminary data for multiple diseases from both mouse models and patient tissue.
|Effective start/end date||5/15/20 → 4/30/21|
- National Institute of Neurological Disorders & Stroke: $1,050,516.00
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