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 #
5R01NS072241-04
Application #
8656451
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
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$355,163
Indirect Cost
$138,600
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Lee, Jieun; Choi, Joseph; Wong, G William et al. (2016) Neurometabolic roles of ApoE and Ldl-R in mouse brain. J Bioenerg Biomembr 48:13-21
Nomura, Mitsunori; Liu, Jie; Rovira, Ilsa I et al. (2016) Fatty acid oxidation in macrophage polarization. Nat Immunol 17:216-7
Li, Zhu; Frey, Julie L; Wong, G William et al. (2016) Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in Osteoblasts. Endocrinology 157:4094-4103
Lei, Xia; Rodriguez, Susana; Petersen, Pia S et al. (2016) Loss of CTRP5 improves insulin action and hepatic steatosis. Am J Physiol Endocrinol Metab 310:E1036-52
Wang, Xiangru; Maruvada, Ravi; Morris, Andrew J et al. (2016) Sphingosine 1-Phosphate Activation of EGFR As a Novel Target for Meningitic Escherichia coli Penetration of the Blood-Brain Barrier. PLoS Pathog 12:e1005926
Lee, Jieun; Choi, Joseph; Aja, Susan et al. (2016) Loss of Adipose Fatty Acid Oxidation Does Not Potentiate Obesity at Thermoneutrality. Cell Rep 14:1308-16
Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan et al. (2016) The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. J Biol Chem 291:16644-58
Bowman, Caitlyn E; Zhao, Liang; Hartung, Thomas et al. (2016) Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series. Mol Cell Biol 36:2089-104
Lee, Jieun; Choi, Joseph; Scafidi, Susanna et al. (2016) Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation. Cell Rep 16:201-12
Lam, Wing Y; Becker, Amy M; Kennerly, Krista M et al. (2016) Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells. Immunity 45:60-73

Showing the most recent 10 out of 21 publications