PROJECTS

Given that neurodegenerative diseases (NDDs) share pathological mechanisms, such as oxidative stress, neuroinflammation and proteinopathy, we propose that focusing on these processes, which occur long before clinical symptoms manifest, could not only slow or halt the progression of NDDs, but also achieve better results compared to current treatments. In this project, we will focus on two targets: the phosphatase DUSP1 and the transcription factor NRF2. DUSP1 is emerging as a promising therapeutic target for treating chronic inflammation and oxidative stress in neurodegenerative conditions. NRF2 and DUSP1 are part of overlapping stress response pathways, so it is likely that they can cooperate in cellular defence mechanisms, especially under conditions of oxidative stress and inflammation.

From a multidisciplinary approach around drug R&D, with research groups belonging to the Instituto de Química Médica - CSIC IQM-CSIC, the Universidad Autónoma de Madrid and the Instituto de Investigación Biomédica Sols-Morreale Sols (UAM-CSIC), the following objectives will be addressed: optimization, synthesis and scale-up of hit compounds obtained as inhibitors of NRF2-KEAP1 and NRF2-βTrCP protein-protein interaction; in vitro characterization of the optimized compounds as NRF2 inducers, testing the efficacy of binding to pharmacological targets in vivo in the brain by means of target engagement studies, pharmacokinetic (ADMET) and toxicity characterization of the selected compounds and evaluation of the lead compounds in in vitro and in vivo tauopathy models.

Learn more about this project on their website.

Given the urgent need to find effective therapies to treat neurodegenerative diseases, especially for the most prevalent ones such as Alzheimer's disease and other tauopathies, non-neuronal cells of the central nervous system are gaining attention as contributors to their pathogenesis and development. Therefore, this project aims to characterize the microglia-astrocyte interrelationship in the context of tauopathy and its impact on tau protein-mediated toxicity in order to define new therapeutic targets.