Guwiyang Wurra--'Fire Mouse': a global gene knockout model for TSPO/PBR drug development, loss-of-function and mechanisms of compensation studies

Ryan J Middleton; Guo-Jun Liu; Richard B Banati

doi:10.1042/BST20150039

Guwiyang Wurra--'Fire Mouse': a global gene knockout model for TSPO/PBR drug development, loss-of-function and mechanisms of compensation studies

Biochem Soc Trans. 2015 Aug;43(4):553-8. doi: 10.1042/BST20150039. Epub 2015 Aug 3.

Authors

Ryan J Middleton¹, Guo-Jun Liu², Richard B Banati²

Affiliations

¹ Life Sciences, Australian Nuclear Science and Technology Organisation, New Illawarra Road, Lucas Heights, NSW 2234, Australia ryan.middleton@ansto.gov.au.
² Life Sciences, Australian Nuclear Science and Technology Organisation, New Illawarra Road, Lucas Heights, NSW 2234, Australia National Imaging Facility, Brain and Mind Research Institute and Faculty of Health Sciences, University of Sydney, 94 Mallett Street, Camperdown, NSW 2050, Australia.

PMID: 26551692
DOI: 10.1042/BST20150039

Abstract

The highly conserved 18-kDa translocator protein (TSPO) or peripheral benzodiazepine receptor (PBR), is being investigated as a diagnostic and therapeutic target for disease conditions ranging from inflammation to neurodegeneration and behavioural illnesses. Many functions have been attributed to TSPO/PBR including a role in the mitochondrial permeability transition pore (MPTP), steroidogenesis and energy metabolism. In this review, we detail the recent developments in determining the physiological role of TSPO/PBR, specifically based on data obtained from the recently generated Tspo knockout mouse models. In addition to defining the role of TSPO/PBR, we also describe the value of Tspo knockout mice in determining the selectivity, specificity and presence of any off-target effects of TSPO/PBR ligands.

Keywords: TSPO/PBR; compound development; energy; knockout; metabolism; mitochondria.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Disease Models, Animal
Energy Metabolism*
Inflammation / drug therapy
Inflammation / genetics
Inflammation / metabolism
Isoquinolines / pharmacology
Isoquinolines / therapeutic use
Mice
Mice, Knockout
Mitochondria / metabolism*
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Permeability Transition Pore
Mutation*
Neurodegenerative Diseases / drug therapy
Neurodegenerative Diseases / genetics
Neurodegenerative Diseases / metabolism
Receptors, GABA / genetics*
Receptors, GABA / metabolism
Steroids / biosynthesis*

Substances

6-chloro-2-(4'-iodophenyl)-3-(N,N-diethyl)imidazo(1,2-a)pyridine-3-acetamide
Bridged Bicyclo Compounds, Heterocyclic
Bzrp protein, mouse
Isoquinolines
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Receptors, GABA
Steroids
PK 11195