Main interests
The main interest is to disclose the biochemical pathways and the molecular target(s) involved in the cytoprotective function of carbon monoxide (CO)/heme-oxygenase (HO) following cerebral hypoxia and ischemia. Our group is also interested in understanding the biochemical processes behind the activation of endogenous mechanisms of defense and conditioning-induced tolerance.
The Cell Death and Disease Lab targets cellular processes including apoptosis, autophagy, metabolic shifts and neuronal differentiation. The objective is to integrate all these cellular processes, with a particular focus on mitochondria and redox signaling. Our approaches include experimental models (rodents and cell culture of brain cells) and human samples (plasma) from healthy volunteers and stroke patients, in close collaboration with Neurology: Stroke & Dementia group.
Research Areas
Cerebral ischemia
Stroke is the 1st cause of death in Portugal and 2nd in Europe, leading to enormous social and economical burden. It is caused by the lack of blood supply and the available therapies are based on reperfusion of blood flow with no direct action on brain parenchyma. Furthermore, these therapies present very short time-window for their application, not reaching all stroke patients because their late arrival at hospitals or when stroke onset is not known.
In newborns, perinatal hypoxic-ischemic encephalopathy (HIE) is caused by birth asphyxia or uterine and fetal blood flow interruption, corresponds to 23% of all neonatal deaths worldwide, and is one of the top 20 leading causes of burden of disease in all age groups (WHO). Despite being a disease with an enormous impact, the single approved clinical therapy is hypothermia and also presents a short time window for its application.
Carbon monoxide
Carbon monoxide (CO) is an endogenous gasotransmitter produced by the activity of haem-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.
Remote ischemic conditioning
Conditioning (also known as hormesis) is a procedure by which a noxious stimulus below damage threshold is applied to a tissue or system. Without causing any damage, endogenous mechanisms of defense are activated, promoting tolerance and cytoprotection. Remote ischemic conditioning (RIC) is the ischemic conditioning of non-vital organs with low-risk (such as arms) that provide protection to another organ (such as the brain). In experimental models, RIC was shown to trigger self-protective pathways in the brain and several potential mechanisms have been postulated: inhibition of neuroinflammation, activation of anti-apoptotic and anti-oxidant pathways, mitochondrial protection and decrease of blood brain barrier permeability.
Objectives of our research group
(i) The use of endogenous CO or low doses of exogenous CO to target brain parenchyma and improve brain cell function following ischemia and reperfusion. The main targeted molecular mechanisms are: CO control of brain cell metabolism (reinforcement of oxidative metabolism based hypothesis) and CO support on glia-neuron signaling to sustain neuronal plasticity/survival.
(ii) To develop a cost-effective and alternative therapy for stroke patients based on remote ischemic post-conditioning for the activation of endogenous mechanisms of defence and targeting brain parenchyma. Likewise, the underlying mechanisms of remote ischemic conditioning are also under study.
(iii) To identify novel plasma circulating biomarkers for allowing stroke onset prediction and to anticipate long-term prognosis, which is of greater importance for therapy decision and long term clinical planning.
Experimental models:
• Primary culture of astrocytes, neurons, microglia and cerebral endothelial cells;
• Primary culture and cell lines of cardiomyocytes;
• Human embryonic carcinoma stem cell line;
• Organotypic cultures of hippocampus and cortex;
• Isolated mitochondria from brain and heart (cell free systems);
• In vivo rodent cerebral ischemia (perinatal ischemia)
Our lab has another research focus in the field of Type 2 diabetes (T2D) conducted by the senior post-doctoral fellow Ines Mollet. This research aims to achieve remission and prevention of type 2 diabetes by investigating enteric neuroendocrine signal transduction pathways in rodent models of type 2 diabetes and human biopsies. This is done using omics approaches for target selection followed by ex-vivo and in-vitro validation of signal transduction networks.
Discover more about the Cell Death and Disease Lab:
Projects
European Union’s Horizon Twinning project 2020 (No 811087)
“LYSOCIL: Excel in Rare Diseases’ Research: Focus on LYSOsomal Disorders and CILiopathies”
PTDC/MEC-NEU/28750/2017
“BistroPC - Remote ischemic post-conditioning in acute phase of ischemic stroke: disclosing novel circulating biomarkers and clinical trial for improving outcome”
PI: Miguel Viana-Baptista and Co-PI: Helena LA Vieira
"Remote ischemic per-conditioning in acute stroke – clinical trial for improving outcome and disclosing novel circulating biomarkers"
Funded by iNOVA4Health Unit
PI: Helena L. A. Vieira and Miguel Viana Baptista
FCT-ANR/NEU-NMC/0022/2012 - “Translational and mechanistic approaches on carbon monoxide as a modulator of neuroinflammation and neuroprotection in glial cells”
Funded by “Fundação para a Ciência e a Tecnologia” and “Agence Nationale pour la Recherche”
PI: Helena L.A. Vieira and Roberto Motterlini
ANR-FCT/BEX-BCM/0001/2013 - “Mechanisms of cardioprotection by berries driven polyphenols”
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)
Municipal Prize for Young Scientists, County of Oeiras 2011 – “Começar em Oeiras” funded by Câmara Municipal de Oeiras, Portugal
COST Action BM 1005 “Gasotransmitters: from basic science to therapeutic applications (ENOG: European Network on Gasotransmitters)” (2011-2014) – Helena L.A: Vieira member of Management Committee.
PTDC/SAU-NEU/089747/2008 - “Preconditioning triggered by Carbon monoxide: new strategies to prevent brain damage due to hypoxia-ischemia and reperfusion”
Funded by “Fundação para a Ciência e a Tecnologia”
PI: Helena L.A. Vieira
PTDC/SAU-NEU/64327/2006 - “Carbon monoxide as neuroprotector against hypoxia-ischemia and reperfusion”
Funded by “Fundação para a Ciência e a Tecnologia”
PI: Helena L.A. Vieira
PTDC/SAU-TOX/112264/2009 - “Chronic Intermittent Eucapnic Hypoxia: systemic effects and evaluation of anti-hypertensive drugs efficacy”
Funded by “Fundação para a Ciência e a Tecnologia”
PI: Emília C. Monteiro
PTDC/MEC-NEU/28750/2017
“BistroPC - Remote ischemic post-conditioning in acute phase of ischemic stroke: disclosing novel circulating biomarkers and clinical trial for improving outcome”
PI: Miguel Viana-Baptista and Co-PI: Helena LA Vieira
"Remote ischemic per-conditioning in acute stroke – clinical trial for improving outcome and disclosing novel circulating biomarkers"
Funded by iNOVA4Health Unit
PI: Helena L. A. Vieira and Miguel Viana Baptista
Funding: British Society for Neuroendocrinology - Project Support Grant (12/2017): “Nervous system signalling in the diabetic gut - Links between disrupted nutrient sensing and GABAergic signals”. Students Master student Miguel Mira (BSc)
FCT-ANR/NEU-NMC/0022/2012 - “Translational and mechanistic approaches on carbon monoxide as a modulator of neuroinflammation and neuroprotection in glial cells”
Funded by “Fundação para a Ciência e a Tecnologia” and “Agence Nationale pour la Recherche”
PI: Helena L.A. Vieira and Roberto Motterlini
ANR-FCT/BEX-BCM/0001/2013 - “Mechanisms of cardioprotection by berries driven polyphenols”
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)
Selected Publications
- Wang Z, Figueiredo-Pereira C, Oudot C, Vieira HL, Brenner C (2017) Mitochondrion: A Common Organelle for Distinct Cell Deaths? Int Rev Cell Mol Biol. 2017;331:245-287. doi: 10.1016/bs.ircmb.2016.09.010. Epub 2017 Jan 2.
- Wilson JL, Bouillaud F, Almeida AS, Vieira HL, Ouidja MO, Dubois-Randé JL, Foresti R, Motterlini R. (2017) Carbon monoxide reverses the metabolic adaptation of microglia cells to an inflammatory stimulus. Free Radic Biol Med. 2017 Jan 18. pii: S0891-5849(17)30031-X. doi: 10.1016/j.freeradbiomed.2017.01.022. [Epub ahead of print]
- Almeida AS, Vieira HL.(2016) Role of Cell Metabolism and Mitochondrial Function During Adult Neurogenesis.Neurochem Res. 2016 Dec 21. doi: 10.1007/s11064-016-2150-3. [Epub ahead of print]
- Queiroga CS, Alves RM, Conde SV, Alves PM, Vieira HL. (2016) Paracrine effect of carbon monoxide: astrocytes promote neuroprotection via purinergic signaling. J Cell Sci. 2016 Jul 6. pii: jcs.187260. [Epub ahead of print]
- Pedroso D, Nunes AR, Diogo LN, Oudot C, Monteiro EC, Brenner C, Vieira HL. (2016) Hippocampal neurogenesis response: what can we expect from two different models of hypertension? Brain Res. 2016 May 25. pii: S0006-8993(16)30407-3. doi: 10.1016/j.brainres.2016.05.044. [Epub ahead of print]
- Almeida AS, Soares NL, Vieira M, Gramsbergen JB, Vieira HL. 216. Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death. PLoS One. 2016 May 4;11(5):e0154781. doi: 10.1371/journal.pone.0154781. eCollection 2016.
- Almeida AS, Sonnewald U, Alves PM, Vieira HL. (2016) Carbon monoxide improves neuronal differentiation and yield by increasing the functioning and number of mitochondria. J Neurochem. 2016 Apr 29. doi: 10.1111/jnc.13653. [Epub ahead of print]
- Klionsky DJ, et al. (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016 Jan 2;12(1):1-222.
Book chapters
- Carlos C. Romão and Helena L. A. Vieira in "Organometallic Chemistry: Recent Advances, ICOMC Silver/Gold Jubilee Book", A. J. L. Pombeiro Editor, J. Wiley, 2013 (in press) ISBN: 9781118510148
- Carlos C. Romão and Helena L. A. Vieira, Metal Carbonyl Pro-drugs: CO delivery and beyond. in Bioorganometallics, G. Jaouen and M. Salmain Eds, Wiley-VCH, 2nd edition, 2013 in press
Collaborations
• Miguel Viana-Baptista, MD PhD, CEDOC - See More
• Roberto Motterlini, University of Paris-Est, FRANCE - See more
• Paula M. Alves, PhD Animal Cell Technology Unit, IBET and ITQB Universidade Nova de Lisboa, PORTUGAL - See More
• Alessandro Vercelli, MD PhD, Universidà degli studi di Torino, ITALY - See more
• Catherine Brenner-Jan, PhD, Faculté de Pharmacie, Université de Paris-Sud, France - See more
• Emília Monteiro, MD, PhD, Lisbon Medical School, Universidade Nova de Lisboa, PORTUGAL - See More
• Sílvia Conde, PhD, Lisbon Medical School, Universidade Nova de Lisboa, PORTUGAL - See More
• Patricia Boya, PhD, Centro de Investigaciones Biológicas, CIB-CSIC, Madrid, SPAIN - See more
• Carlos Romão, PhD, ITQB, PORTUGAL - See More
• Carlos Duarte, PhD, Universidade de Coimbra, PORTUGAL - See More at FCTUC or at CNC - See More
Team photos
