Intracellular long chain fatty acyl-CoAs provide the substrate for acylation reactions for membrane phospholipid biosynthesis, protein palmitoylation and cellular oxidative energy among others. Neurons have unique roles for lipids that are distinct from other cell types and are equipped with specialized machinery for regulating intracellular lipids. Although it is widely appreciated that the lipid composition of neurons is critical for human development and defects in lipid metabolism result in severe and debilitating neurological disease, there is a dearth of understanding about how neurons regulate intracellular lipid metabolism at a fundamental level. We have found that neuronal-specific acyl-CoA thioesterases are critical for neuronal development and function. We hypothesize that acyl-CoA thioesterase 7 (ACOT7) functions at an essential regulatory step for fatty acid utilization in neurons and that dysregulation of ACOT7 results in neurological dysfunction. To test this hypothesis we propose three specific aims: 1) Determine the role of ACOT7 in regulating cellular lipid metabolism. 2) Determine the neuron-specific role of ACOT7 in lipid metabolism and 3) Determine the role of ACOT7 in neurological pathophysiology.

Public Health Relevance

The rationale for these studies is that understanding the mechanisms for neuron-specific regulation of lipid metabolism will provide insight into the role of lipids in normal neurophysiology and development, and also for neurodegenerative diseases such as ALS, Parkinson's, and Alzheimer's disease which have been shown to have underlying metabolic complications. These studies will form the basis for understanding the contribution of lipids to neurological disease and enable the development of targeted therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072241-03
Application #
8461179
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Sutherland, Margaret L
Project Start
2011-07-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$385,995
Indirect Cost
$149,280
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rodriguez, Susana; Ellis, Jessica M; Wolfgang, Michael J (2014) Chemical-genetic induction of Malonyl-CoA decarboxylase in skeletal muscle. BMC Biochem 15:20
Ellis, Jessica M; Wong, G William; Wolfgang, Michael J (2013) Acyl coenzyme A thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity. Mol Cell Biol 33:1869-82
Wei, Zhikui; Peterson, Jonathan M; Lei, Xia et al. (2012) C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes. J Biol Chem 287:10301-15
Miyamoto, Takafumi; DeRose, Robert; Suarez, Allison et al. (2012) Rapid and orthogonal logic gating with a gibberellin-induced dimerization system. Nat Chem Biol 8:465-70
Rodriguez, Susana; Wolfgang, Michael J (2012) Targeted chemical-genetic regulation of protein stability in vivo. Chem Biol 19:391-8