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.
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.
|Agusti, Ana; Dziedzic, Jennifer L; Hernandez-Rabaza, Vicente et al. (2014) Rats with minimal hepatic encephalopathy due to portacaval shunt show differential increase of translocator protein (18 kDa) binding in different brain areas, which is not affected by chronic MAP-kinase p38 inhibition. Metab Brain Dis 29:955-63|
|Coughlin, Jennifer M; Wang, Yuchuan; Ma, Shuangchao et al. (2014) Regional brain distribution of translocator protein using [(11)C]DPA-713 PET in individuals infected with HIV. J Neurovirol 20:219-32|
|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|
|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|
|Chen, Ming-Kai; Guilarte, Tomas R (2008) Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther 118:1-17|