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Transient inactivation of hypothalamic hormone release to prevent post-traumatic stress sensitization

Project description

Therapeutic targets against post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) may develop in people who have experienced a traumatic event. Although feelings of shock, fear, and stress will normally go away over time, people with PTSD experience symptoms for longer and lose their ability to go on with their daily lives. Scientists of the ERC-funded SECRET-DOCK project had previously identified a neurocircuit in the brain that sensitises one to stress. They propose that this pathway may serve as a starting point for the identification of therapeutic targets. Researchers will screen small molecules as potential inhibitors against proteins implicated in this pathway, which is responsible for PTSD.

Objective

Stress is the foremost consequence of human life and became a pressing societal burden through the many sensory and societal pressures that have evolved during the past decades. Severe stress induces maladaptive changes in the brain that clinically manifest as post-traumatic stress disorder (PTSD). Despite ~4% of the population presenting PTSD, only symptomatic therapies are available. In the ’SECRET-CELLS’ ERC award, we have identified a multimodal neurocircuit that induces brain-wide sensitization to stress through the sequential recruitment of hypothalamic, midbrain and then cortical neuronal circuits. Particularly, we identified protein targets that can simultaneously affect hormone and neurotransmitter release within this circuit and whose knock-out makes mice stress resilient. Therefore, we used unbiased proteomics to select protein interactors that participate in the related signaling cascades, determined the biochemical parameters of any such interaction and the X-ray structures of the relevant protein complexes. Moreso, a high-throughput screen was established to identify inhibitors. Here, we will apply this knowledge to use interacting proteins as templates for small-molecule inhibitor discovery and hit optimization. Subsequently, we will profile the pharmacology and cytotoxicity of the candidates in vitro. Thus, we will take critical steps towards developing a ‘circuit breaker’ that can inactivate the neuronal contingents that are causal to the development of PTSD. Thereby, we will offer a fundamentally novel framework for pharmacotherapy.

Host institution

MEDIZINISCHE UNIVERSITAET WIEN
Net EU contribution
€ 150 000,00
Address
SPITALGASSE 23
1090 Wien
Austria

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Region
Ostösterreich Wien Wien
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Beneficiaries (1)