AMP-activated protein kinase (AMPK) functions as a key energy sensor and metabolic rheostat to maintain cells'energy needs, largely through maintaining ATP levels. Disruption of AMPK signaling leads to neuronal death, while mutations in human AMPK subunits cause the fatal cardiac disorder, Wolff-Parkinson-White syndrome. We are using a genetic model in Drosophila to identify genes that modulate AMPK signaling in vivo. Using this novel forward genetic screen we have identified nucleoside diphosphate kinase (NDPK) as a potential modifier and target of AMPK signaling. We have found a new mechanism whereby AMPK-dependent phsphorylation of NDPK turns it off. This off switch site corresponds to a location mutated in advanced human neuroblastoma. Through identification of new genes that suppress AMPK RNAi lethality, and making a genetic model of mutations in AMPK that cause human disease, we hope to identify both new mechanisms and molecules that modulate AMPK function in vivo.

Public Health Relevance

We are identifying new genes that mediate AMP-activated protein kinase (AMPK) signaling. Mutations in AMPK cause human Wolff-Parkinson-White syndrome, a fatal cardiac disorder. In addition, AMPK is a pre-clinical Type 2 diabetes target so identifying genes that affect AMPK function could lead to better treatment of diabetes/metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080108-08
Application #
8596854
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Mamounas, Laura
Project Start
2004-12-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
8
Fiscal Year
2014
Total Cost
$288,277
Indirect Cost
$91,402
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Onyenwoke, Rob U; Sexton, Jonathan Z; Yan, Feng et al. (2015) The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase. Biochem J 470:331-42
Yi, Na Young; He, Qingping; Caligan, Thomas B et al. (2015) Development of a Cell-Based Fluorescence Polarization Biosensor Using Preproinsulin to Identify Compounds That Alter Insulin Granule Dynamics. Assay Drug Dev Technol 13:558-69
Onyenwoke, Rob U; Brenman, Jay E (2015) Lysosomal Storage Diseases-Regulating Neurodegeneration. J Exp Neurosci 9:81-91
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Sinnett, Sarah E; Sexton, Jonathan Z; Brenman, Jay E (2013) A High Throughput Assay for Discovery of Small Molecules that Bind AMP-activated Protein Kinase (AMPK). Curr Chem Genom Transl Med 7:30-8
Swick, Lance L; Kazgan, Nevzat; Onyenwoke, Rob U et al. (2013) Isolation of AMP-activated protein kinase (AMPK) alleles required for neuronal maintenance in Drosophila melanogaster. Biol Open 2:1321-3
Kern, Jeannine V; Zhang, Yao V; Kramer, Stella et al. (2013) The kinesin-3, unc-104 regulates dendrite morphogenesis and synaptic development in Drosophila. Genetics 195:59-72
Klionsky, Daniel J (author list too long to display - see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544
Braco, Jason T; Gillespie, Emily L; Alberto, Gregory E et al. (2012) Energy-dependent modulation of glucagon-like signaling in Drosophila via the AMP-activated protein kinase. Genetics 192:457-66
Onyenwoke, Rob U; Forsberg, Lawrence J; Liu, Lucy et al. (2012) AMPK directly inhibits NDPK through a phosphoserine switch to maintain cellular homeostasis. Mol Biol Cell 23:381-9

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