Neurons have unique roles for lipids that are distinct from other cell types and are equipped with specialized machinery for regulating intracellular lipid metabolism. Although it is widely appreciated that the lipid composition of neurons is criticl 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. Using tissue specific transgenic and knockout mouse models we have discovered that neurons regulate fatty acid flux and prevent lipotoxicity by hydrolyzing long chain acyl-CoAs to free fatty acid and CoA. This is mediated by the neuron-specific Acyl-CoA Thioesterase 7 (ACOT7). The loss of ACOT7 in mice and humans results in behavioral deficits and neurodegenerative disease. We have developed a new model describing the coordinated metabolism of fatty acids within the nervous system between neurons and astrocytes. We hypothesize that this is mediated by acyl-CoA hydrolysis within the neuron and fatty acid ?-oxidation within the astrocyte. Because of the critical importance of fatt acids to brain function and pathophysiology, a deeper understanding of fatty acid metabolism in the nervous system is greatly needed. The studies described herein will detail these fundamental unanswered questions. To test these hypotheses we propose two specific aims: 1) Determine the neuroprotective role and regulation of ACOT7. 2) Determine the roles and requirements for brain fatty acid oxidation. The long-term goal of this project is to elucidate the molecular mechanisms employed by the nervous system to regulate the metabolism of fatty acids. The expectation is that our proposed studies will describe new mechanisms for how fatty acid metabolism is regulated in the nervous system and more broadly, advance our understanding of the role of lipid homeostasis in neurological disease.

Public Health Relevance

The rationale for these studies is that understanding the mechanisms for the regulation of lipid metabolism in the nervous system will provide insight into basic neurochemistry and also for neurodegenerative diseases that have underlying metabolic complications. These studies will form the basis for understanding the contribution of lipids to neurological disease and enable the development of rational nutritional therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072241-07
Application #
9274053
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Sutherland, Margaret L
Project Start
2011-07-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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