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Trace Amine-Associated Receptor 1 (TAAR1) agonists in a chemogenetic/molecular imaging model of increased dopamine synthesis capacity (Ki)

Project description

Trace amine-associated receptor 1 as a new molecular target in schizophrenia investigation

The study of the functional role of striatal dopamine (DA) signalling is necessary due to its wide-ranging impact on learning, motivational and motor processes. DA over-reactivity is the most well-established pathophysiological mechanism underlying schizophrenia. The EU-funded TACtIK project aims to introduce an innovative chemogenetic/positron emission tomography (PET) imaging model of striatal DA over-reactivity to test the efficacy of new antipsychotic compounds that target the trace amine-associated receptor 1 (TAAR1). The goal is to develop a mouse model of increased pre-synaptic DA synthesis capacity (Ki) in the striatum and to determine if TAAR1 agonists decrease striatal Ki in the model and in patients with a diagnosis of schizophrenia.

Objective

My research plan aims at generating an innovative chemogenetic/positron emission tomography (PET) imaging translational model of striatal dopamine (DA) over-reactivity, the most well-established pathophysiological mechanism underlying schizophrenia. I will use this platform to test the therapeutic efficacy of antipsychotic compounds with a totally new mechanism of action, i.e. targeting the trace amine-associated receptor 1 (TAAR1). Pre-clinical findings will have immediate translation to humans. I envisage a two-fold utility of this platform for the scientific community: 1) development of innovative therapeutic strategies for psychotic disorders; 2) ask fundamental questions about the pathophysiology of schizophrenia.
A substantial share of patients treated with available antipsychotics do not respond and/or experience undesirable side effects. Available antipsychotics do not target the neurobiological mechanisms underlying schizophrenia symptoms, i.e. increased pre-synaptic DA synthesis capacity (Ki) in the striatum. They rather rely on blockade of DA receptors post-synaptically, possibly causing iatrogenic DA super-sensitivity. Therefore, there is a quest for improved therapeutic strategies, addressing DA over-reactivity. A novel target is represented by TAAR1, a G protein-coupled receptor that has been found to crosstalk with the DAergic system. Based on these premises, the objectives of this project are:
-Work package 1. To develop a chemogenetic translational mouse model of increased striatal Ki. We will use [18F]-FDOPA PET imaging to determine if selective manipulation of midbrain neuron firing increases Ki.
-Work package 2. To determine if TAAR1 agonists (TAAR1 toolbox) decrease striatal Ki in the model from WP1. We will ascertain whether TAAR1 is necessary for the effect on Ki, using TAAR1 knock-out (KO) mice.
-Work package 3. To determine whether TAAR1 toolbox modulate Ki in patients with a diagnosis of schizophrenia, applying [18F]-FDOPA PET imaging.

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Coordinator

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Net EU contribution
€ 212 933,76
Address
South kensington campus exhibition road
SW7 2AZ London
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
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Other funding
€ 0,00