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
Sinnett, Sarah E; Brenman, Jay E (2014) Past strategies and future directions for identifying AMP-activated protein kinase (AMPK) modulators. Pharmacol Ther 143:111-8
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