The long-term goal of this research is to continue the validation and application of the Translocator Protein 18 kDa (TSPO), previously called the peripheral benzodiazepine receptor as a biomarker of neurotoxicity, neuroinflammation and neurodegeneration. While TSPO is being used in preclinical and clinical studies to detect and monitor brain injury and inflammation, the function of TSPO in microglia and astrocytes, the glial cell types that express and upregulate TSPO levels is not currently known. The proposed studies have several inter-related goals. First, we have discovered that in primary microglia, TSPO may be associated with NADPH oxidase (NOX) and mechanistic studies proposed in Specific Aim 1 are planned to extend this finding and to further understand the TSPO/NOX interaction.
In Specific Aim 2 we propose studies to understand the function of TSPO in astrocytes. While the function of TSPO in microglia may be associated with the innate immune response, we hypothesize that the function of TSPO in astrocytes may be associated with the synthesis of neurosteroids. An understanding of the function of TSPO in microglia and astrocytes will assist in devising therapeutic approaches for mitigating neuroinflammation in neurodegenerative disease. Finally in Specific Aim 3 we proposed studies to validate and apply TSPO as a biomarker of neurotoxicity in the fetal and early postnatal brain. While most studies to date have used brain tissue from adult animals or humans, we have evidence that TSPO may serve as a biomarker of brain injury in the fetal brain. These studies will use a novel TSPO-GFP mouse model that will significantly facilitate the detection of brain injury in vivo and ex vivo. Te development of novel methods to screen the neurotoxic potential of chemicals is of high priority as articulated by Dr. Francis Collins, the present director of the National Institutes of Health. Thus, the proposed studies have significant translational implications to the human condition. The proposed studies will use a variety of methodologies ranging from cell culture to imaging and are in line with research goals of the National Institute of Environmental Health Sciences and the National Toxicology Program.

Public Health Relevance

The development of a novel method such as TSPO to screen the neurotoxic potential of chemicals will help minimize human neurological health risks. We have evidence that TSPO can serve as an early and sensitive biomarker of brain injury and recovery to study human neurodegenerative disease. A mechanistic understanding on the function of TSPO in microglia and astrocytes will assist in devising therapeutic strategies to mitigate brain injury and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007062-16
Application #
8728852
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Hollander, Jonathan
Project Start
1995-09-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
16
Fiscal Year
2014
Total Cost
$298,584
Indirect Cost
$110,484
Name
Columbia University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Loth, Meredith K; Choi, Judy; McGlothan, Jennifer L et al. (2016) TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology. Neurobiol Dis 85:174-86
Cole, Toby B; Coburn, Jacki; Dao, Khoi et al. (2016) Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain. Toxicology 374:1-9
Guilarte, Tomás R; Loth, Meredith K; Guariglia, Sara R (2016) TSPO Finds NOX2 in Microglia for Redox Homeostasis. Trends Pharmacol Sci :
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Fairweather, DeLisa; Coronado, Michael J; Garton, Amanda E et al. (2014) Sex differences in translocator protein 18 kDa (TSPO) in the heart: implications for imaging myocardial inflammation. J Cardiovasc Transl Res 7:192-202
Fairweather, DeLisa; Guilarte, Tomás R; Cooper Jr, Leslie T (2014) Biomarker and more: can translocator protein 18 kDa predict recovery from brain injury and myocarditis? Biomark Med 8:605-7
Kang, N; Peng, H; Yu, Y et al. (2013) Astrocytes release D-serine by a large vesicle. Neuroscience 240:243-57

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