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Brain research

 

The development of drugs for human central nervous system (CNS) diseases has traditionally relied on genetically engineered mouse models (GEMMs). However, the CNS is highly complex and also, GEMMs’ phenotypes often diverge from that of human diseases. These factors represent the main obstacle to the translation of CNS drugs pre-clinical to the clinical trials.

Therefore, 3D in vitro models are useful complementary tools towards more accurate evaluation of drug candidates in pre-clinical stages, as they present an intermediate degree of complexity in terms of cell-cell and cell-matrix interactions, between the traditional 2D monolayer culture conditions and the complex brain and can be a better starting point for the analysis of the in vivo situation. We have been developing brain models using primary cultures of rat brain cells and cultures of differentiated human embryonal carcinoma cell lines and human neural stem cells.

Furthermore, we are exploring our 3D brain cell models to reveal additional layers of information, usually concealed by the high complexity of interactions that occur in vivo. Using metabolic flux analysis tools and data on 13C enrichment into intra and extracellular metabolites (NMR and GC-MS analysis) we have been quantifying the metabolic effects caused by specific insults which frequently occur in the brain.

A research "niche” headed by Dr Helena L.A. Vieira, a senior Post-doc in the lab, is focused on applying these cell models for understanding the cellular and biochemical pathways involved in cerebral cell reprogramming by carbon monoxide (CO). CO is known to be toxic. Nevertheless, in low levels this endogenously produced molecule has anti-inflammatory, anti-proliferative or anti-apoptotic effects in several tissues. Cerebral hypoxia-ischemia and reperfusion (HIR) is the most common cause of disability and death worldwide. However, no effective therapy to aid recovery from brain damage is available, making the development of novel therapeutic strategies urgent. Using HIR as the pathological model, we have demonstrated that CO prevents apoptosis in astrocytes and neurons, both in vitro and in vivo. Currently, we are investigating the cross-talk between apoptosis, necrosis, autophagy, differentiation and metabolic shifts in a transversal manner, integrating all these cellular processes.

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