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UC.PT

IBILI

Pharmacology and Experimental Therapeutics

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Coordinator: Francisco Ambrósio

Ageing, diseases and drugs might have a tremendous impact in the physiology of several organs compromising their function. Despite the multitude of therapies available to treat many disorders, the outcome of several therapies is not satisfactory. Therefore, the development of improved therapies is crucial to ameliorate patient health. Our group has been focused in elucidating the molecular and cellular mechanisms underlying the pathogenesis of disorders affecting the brain, retina, heart and kidney, as well as in identifying new potential drug targets and more efficient therapeutic options.

The impact of drugs of abuse in brain and retina is far from being elucidated. We have been interested in amphetamine derivatives, methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA). We intend to elucidate the mechanisms underlying the effects of METH on brain and blood-brain barrier, giving emphasis to neuroinflammatory processes, the crosstalk between different cell types, and astrocyte-related glutamatergic/gabaergic function. We also aim evaluating memory deficits triggered by METH and the possible therapeutic effect of modulating the neuropeptide Y (NPY) system. The effect of METH on progenitor cell survival, proliferation, and differentiation is also being investigated. One of the major concerns with METH abuse is that METH addicts are more prone to develop Parkinson’s disease (PD). Using a mice model of PD, we are evaluating the role of alpha-synuclein and RAGE (Receptor for Advanced Glycation Endproducts) axis on striatal degeneration induced by the dopaminergic toxins METH and MPTP. Moreover, since the impact of MDMA in the retina is virtually unknown, we have also been investigating the effects of MDMA in retinal physiology.

Regarding the eye, our main research interests are focused in two non-curable retinal degenerative diseases, diabetic retinopathy and glaucoma, which are leading causes of vision loss. The general goals are to elucidate the molecular and cellular mechanisms underlying neuronal, glial, endothelial (blood-retinal barrier and endothelial progenitor cell) dysfunction and degeneration, identify potential therapeutic targets and clarify the mechanisms of action of drugs that exert protective effects in the retina. In both diabetic retinopathy and glaucoma, we have been investigating the mechanisms underlying neuroinflammatory processes, how inflammation can contribute to retinal cell dysfunction/death, and explore new targets in microglial cells to control neuroinflammation, such as NPY, adenosine, and endocannabinoid systems, as well as Src kinase and vitamin C transporter.

In addition to lowering intraocular pressure, neuroprotective tools against ganglion cell degeneration have been considered as potential and promising strategies to treat glaucoma. We are exploring the neuroprotective potential of manipulating NPY, adenosine and endocannabinoid systems against retinal ganglion cell degeneration.

Still regarding diabetes complications, the hippocampus, an important player on learning and memory processes, has been recognized as presenting a high degree of susceptibility to diabetes. We are investigating the impact of diabetes in hippocampus, giving particular attention to presynaptic changes and neuroinflammatory processes, to provide a more comprehensive neurotoxic profile.

Part of the group has been involved in experimental and clinical studies related to pharmacologic and therapeutic options in cardiorenal disorders, including chronic kidney disease, nephropathy induced by cyclosporine A, diabetic nephropathy, atherosclerosis/dyslipidaemia, as well as bladder cancer. The main goals are to elucidate the mechanisms underlying the pathophysiology of those disorders, estimate whether drug-induced toxicity could be ameliorated, and evaluate the efficacy of drugs, alone or in combination, for disease prevention/treatment.

The concept that tumors are maintained by cancer stem-like cells (CSC), which have been considered a source of tumor recurrence, is controversial and remains to be clarified. Our main goals are elucidating the role of CSC in cancer initiation and progression, in therapy response in solid tumors, namely osteosarcoma and bladder cancer, as well as to identify the mechanisms of therapy resistance that operate in CSC and the signaling pathways required for stem cell maintenance, in order to identify potential therapeutic targets specific for these cells, since conventional therapies target bulk tumor cells and have limited impact in CSC.

Groups

Ana Paula Silva

Célia Gomes

Flávio Reis

Frederico Pereira

Luís Almeida

Rosa Fernandes