Molecular Mechanisms of Disease
Stroke is the 1st cause of death in Portugal and 2nd in Europe. Ischemic stroke results from the lack of blood supply (ischemia), which limits oxygen and nutrients, leading to brain damage and neuronal death. Current therapies (thrombolysis and mechanical thrombectomy) re-establish blood flow but do not directly target damaged brain cells. In newborns, perinatal hypoxic-ischemic encephalopathy is caused by birth asphyxia or fetal blood flow interruption, corresponds to 23% of neonatal death and is one of the top 20 leading causes of burden of diseases (WHO). Despite its enormous impact, systemic hypothermia is the single approved clinical therapy. Thus, there is an urgent need for efficient therapies to rescue brain tissue. Our broaden scientific question tackles the mechanisms underlying ischemia-reperfusion events in brain cells, by targeting several cellular processes: apoptosis, inflammation, autophagy, metabolic shifts, redox signaling and neuronal differentiation. The final objective is to integrate this knowledge and develop new approaches for protecting brain tissue based on: (i) the cytoprotective function of carbon monoxide /heme-oxygenase and (ii) the activation of endogenous mechanisms of defense and conditioning-induced tolerance.
Novel carbon monoxide-based strategies against ischemic stroke: modulation of brain cell metabolism and glia-neuron signaling
Carbon monoxide (CO) is an endogenous gasotransmitter produced by the activity of heme-oxygenase (HO), a stress response enzyme. CO is associated with maintenance of homeostasis and cytoprotection in several tissues, including brain. In fact, CO has anti-apoptotic properties in neurons and in astrocytes, promotes neurogenesis, and reduces neuroinflammation in microglia. Recently, our lab has demonstrated a new biological property of CO: modulation of cell metabolism, which is implicated in prevention of cell death, control of neurogenesis and regulation of inflammation. The final aim is to develop novel mechanistic and translational approaches against stroke based on modulation of brain cell metabolism and glial-neuron communication, which may eventually lead to novel therapies. In close collaboration with the leading company on CO drug development Proterris, new and advanced CO-releasing molecules are under analysis in different models and biological functions.
Remote ischemic conditioning in acute phase of ischemic stroke – disclosing novel circulating biomarkers and clinical trial for improving outcome
(Pre)-conditioning is promoted by a stimulus that is normally hazard (as ischemia), but when applied below the damage threshold it promotes cytoprotection by activation of endogenous mechanisms of defence. Remote ischemic conditioning (RIC) is the ischemic conditioning of non-vital organs (as arms) that protects another organ, as brain. In experimental models there is evidence of RIC protection in stroke, while clinical trials are needed to evaluate the potential therapeutic value of RIC. Furthermore, there is very few data about how inter-organ communication occurs nor how short cycles of ischemia in the arm can protect the brain in humans. Three mains hypotheses exist: circulating biochemical factors, immune response and/or activation of autonomous nervous system.
This project is develop in close collaboration with Neurology: Stroke & Dementia group of NOVA Medical School, UNL and presents clinical and mechanistic objectives. The clinical objectives are: (i) evaluation of RIC in acute ischemic stroke patients, whether it improves the outcome (brain imaging, neurological tests and clinical parameters) for the development of a cost-effective and alternative therapy for stroke and (ii) identification of novel plasma circulating biomarkers for allowing stroke onset prediction and to anticipate long-term prognosis. For the second objective, RIC is applied in healthy volunteers to study the underlying mechanisms, namely what is activated in the arm that acts on the brain. Plasma circulating factors of healthy subjects are under analysis by proteomic, gasometry and metabolomics, along with functional validation of human conditioned plasma in experimental models.
- Remote ischemic post-conditioning in acute phase of ischemic stroke: disclosing novel circulating biomarkers and clinical trial for improving outcome - PTDC/MEC-NEU/28750/2017, Total funding € 239 900 - PI: Miguel Viana-Baptista and Co-PI: Helena L A Vieira
- Translational and mechanistic approaches on carbon monoxide as a modulator of neuroinflammation and neuroprotection in glial cells - FCT-ANR/NEU-NMC/0022/2012, Total funding € 249 000 - Funded by “Fundação para a Ciência e a Tecnologia” and “Agence Nationale pour la Recherche” - PI: Helena L.A. Vieira and Roberto Motterlini
- Mechanisms of cardioprotection by berries driven polyphenols - ANR-FCT/BEX-BCM/0001/2013, Total funding € 187 800 - Funded by “Fundação para a Ciência e a Tecnologia” and “Agence Nationale pour la Recherche” - PI: Cláudia Santos (iBET) and Catherine Brenner (Université de Paris-Sud), Helena L Vieira responsible for one task
- Preconditioning triggered by Carbon monoxide: new strategies to prevent brain damage due to hypoxia-ischemia and reperfusion, PTDC/SAU-NEU/089747/2008, Total funding € 100 000 - PI: Helena L A Vieira
- Carbon monoxide as neuroprotector against hypoxia-ischemia and reperfusion - PTDC/SAU-NEU/64327/2006, Total funding € 125 000 – PI: Helena L A Vieira