H2020Индивидуална стипендия2021–2023

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

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-09-01 → 2023-08-31
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Рецепторите TAAR1 в мозъка се изследват като нова мишена за лекарства, които да регулират свръхактивността на допамина при шизофрения. Това е важно, защото настоящите антипсихотични средства имат странични ефекти и ефективността им може да намалее с времето.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

Schizophrenia has a worldwide prevalence of 0.2-3.5% and mainly strikes young adults between the ages of 20 and 35, a time when most people are completing their education and establishing themselves as independent adults. This explains the significant burden of schizophrenia to both person and society. Antipsychotic drugs were discovered serendipitously in the 1950s, while their mechanism of action could be elucidated only fifty years later. Using positron emission tomography (PET) imaging, the relationship between dopamine (DA) D2 receptors occupancy and clinical response was demonstrated. Unfortunately, post-synaptic D2 receptor density is not primarily altered in treatment-naïve patients. The major pathophysiological abnormality underlying schizophrenia is pre-synaptic, and consists of increased striatal DA synthesis capacity due to midbrain DA neuron over-activity, as shown by [18F]-FDOPA PET imaging. Prolonged D2 blockade may super-sensitize the system, thus causing tolerance and loss of efficacy, enhancing vulnerability to relapse, and triggering movement disorders. Therefore, in the medical treatment of schizophrenia there is much room for improvement. A promising, novel target is the trace amine-associated receptor 1 (TAAR1), a recently identified G protein-coupled receptor. TAAR1 is widely expressed across the mammalian brain, including the DAergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), the main striatum afferents. Pre-clinical evidence of an interaction between TAAR1 and DA systems has been accumulating at several levels. Different classes of synthetic TAAR1 agonists are currently available. For instance, SEP-363856 (Sunovion Pharmaceuticals) is a TAAR1/5-HT1A agonist that yielded promising results in a phase 2 multisite clinical trial (NCT02969382). The overall objectives of TACtIK were to demonstrate that drugs targeting TAAR1 reduce dopamine synthesis capacity in a rodent model of meso-striatal dopamine overactivity and in people with a diagnosis of schizophrenia.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonКоординаторОбединеното кралство