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Neuroscience and disease

Neuroendocrinology and Aging

Areas of focus

Hypothalamus is a brain region known to regulate basic life functions, such as growth, development, reproduction, circadian rhythms, sleep and is critically involved in feeding, glucose homeostasis and metabolism. The hypothalamus neurons are capable to sense energy and peripheral signals (glucose, insulin, leptin), modifying energy status accordingly. Evidence suggests that the integrity of metabolic sensing mechanisms in hypothalamic neurons is crucial for maintaining metabolic homeostasis and normal aging. It is therefore exciting to suggest that hypothalamic neurons could drive aging and age-related diseases.

In our group we investigate the hypothalamus as an underlying mediator and a target for interventional strategies in counteracting aging and related diseases. In this context the group focuses the research on the following scientific questions and strategies: i) Does caloric restriction (CR) delay aging and age-related diseases through hypothalamus-related mechanisms? ii) Could we delay premature aging of Hutchinson Gilford progeria syndrome (HGPS) rodent models, and normal aging, by targeting the hypothalamus? iii) Hypothalamic changes related to obesity, depression and ageing.

Research Lines

•   Caloric restriction and related mechanisms as anti-aging interventions and neuroprotector
•   Changes in the hypothalamus induced by obesity and aging
•   Hypothalamus has a target for preventing aging
•   Neurogenesis in the Hypothalamus
•   Changes in adipose tissue and hypothalamus induced by hypoxia: relation between sleep apnea syndrome, obesity and aging

Ongoing Projects

•   Endogenous caloric restriction mimetics and related mechanisms (NPY, ghrelin, sirtuins, ataxin-2) in hypothalamus.
     Sara Carmo-Silva, Marisa Marques, André Carvalho, Dina Pereira, Patricia Valério, Célia Aveleira, Pedro Gomes, Cláudia Cavadas

•   Studies on aging models and Hutchinson-Gilford Progeria Syndrome (HGPS) models.
     Sara Carmo Silva, Marisa Marques, Dina Pereira, Célia Aveleira, Cláudia Cavadas

•   MicroRNAs, neurogenesis and hypothalamic regulation.
André Carvalho, Sara Carmo Silva, Célia Aveleira, Cláudia Cavadas

•   Sleep, obesity and aging
     Laetitia Gaspar, Ana Rita Álvaro, Sara Carmo-Silva, Joana Rosmaninho-Salgado, Cláudia Cavadas

•   Delaying neurodegeneration by NPY and caloric restriction approaches.
Cláudia Cavadas; collaboration with Luís Pereira de Almeida

Cláudia Cavadas

Group Leader

Ana Rita Álvaro

PhD

Ana Santos Carvalho

PhD

Antonio Pedro Gomes

PhD

Célia Aveleira

PhD

FCT Investigator

Joana Rosmaninho Salgado

PhD

João Pedro Magalhães

PhD

Magda M Santana

PhD

Dina Pereira

PhD Student

(PDBEB)

Helena Leal

PhD Student

FCT Scholarship FFUC

Marisa Ferreira

PhD Student

FCT Scholarship FFUC

Sara Silva

PhD Student

FCT Scholarship FFUC

Laetitia Gaspar

MSc

André Carvalho

MSc Student

Patrícia Valério

MSc Student

Patrick Silva

MSc Student

Cláudia Rodrigues

BSc Student

Alumni

Facilities and equipment

The lab is located at Rua Larga, Polo I, 2nd Floor – University of Coimbra. The lab is equipped with general cellular and molecular biology equipment. Researchers have access to cell culture rooms, animal facilities, rodent behavior room, microtome, fluorescence microscopy, scanning confocal microscopy, flow cytometry, electrophoresis apparatus, quantitative RT-PCR and HPLC.

Financed projects

Title: "Peripheral NPY reverts HGPS phenotype: a study in human fibroblasts and mouse model”. Grant Funded by Progeria Research Foundation (MA, USA). September 2015-August 2017

COST Action: An integrative action for multidisciplinary studies on cellular structural networks. COST Action. CA15214. National representative Cláudia Cavadas. 2016-2020

Title: “Ghrelin: a novel therapeutic intervention to rescue the phenotype of Hutchinson‐Gilford Progeria Syndrome”. American Progeria Research Foundation. 2015 –2016

Title: “Sleep apnea induces obesity: Why? What is the role of the hypothalamus and the adipose tissue?”. Grant International cooperation programmme: Fundação para a Ciência e a Tecnologia (Portugal) and CAPES (Brasil) “Entidade Financiadora: Fundação para a Ciência e a Tecnologia”. 2013-2015

Pre-clinical study of Depression - Pharmaceutical Company Contract- Tecnimed (Sintra, Portugal). 2013- 2014

Title: “iCALP - Identification of the physiological roles of calpains in the control of cell proliferation and migration in the central nervous system”. FCT project PTDC/SAU-NMC/112183/2009. 2011- 2014

Title: “Mechanisms underlying the effects of nitric oxide on neural stem cell proliferation in brain injury“. FCT project: PTDC/SAU-NEU/102612/2008. 2010- 2013

Title: “Caloric restriction increases lifespan: role of neuropeptide Y on autophagy”. FCT project: PTDC/SAU-FCF/099082/2008. April 2010-July 2013

Title: “Adenosine receptors on adrenal medulla regulation: its role on stress response”. FCT project: PTDC/SAU-NEU/108110/2008). 2010- 2013

Title: “The Neuropeptide Y (NPY) and Dipeptidyl-peptidase IV (DPPIV) as new promising targets on the adipose tissue regulation in obesity”. FCT project: PTDC/SAU‐FCF/102415/2008. 2010 – 2012

Title: "NPY in the retina: Why? and What for?”. FCT project: PTDC/SAU-NEU/73119/2006). 2007 - 2010

Title: "Evaluation of ecstasy toxicity in rat retina: in vitro and in vivo studies". Instituição Financiadora: "Gabinete de Apoio à Investigação" - Faculty of Medicine of the University of Coimbra. 2007

Title: "Crosstalk between catecholamines and neuropeptide Y in human chromaffin cells". FCT project POCTI/SAU-FCF/60399/2004. 2005 - 2008

Science and communication funded projects:

The Brains Go Around the Town” - Brain Awareness Week (BAW) March 2015. Federation of European Neuroscience Societies (FENS) funding.

Science Divulgation Project – “I want more and better cells! (Stem cells: What are they? Where are they? What are they used for?) COMPETE- Ciência viva; January 2011-December 2013

“Brain and mathematics” - Brain Awareness Week (BAW) March 2007; Federation of European Neuroscience Societies (FENS) funding.

Collaborations

Carlos Lopez Otin
Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain

David Sinclair
Harvard Medical School, USA

Joaquim Moita
CHUC, Coimbra, Portugal

Leonard Guarente
Glenn Laboratory for the Science of Aging, Massachusetts Institute of Technology, Cambridge, USA.

Licio Velloso
University of Campinas, Brazil

Ruben Nogueiras
CIMUS, University of Santiago de Compostela, Spain

Xavier Nissan
Item, Paris, France

Flávio Reis
IBILI, Faculty of Medicine, University of Coimbra, Portugal

Selected Publications

Cunha-Santos J, Duarte-Neves J, Carmona V, Guarente L, Pereira de Almeida L* & Cavadas C*. Caloric restriction blocks neuropathology and motor deficits in Machado-Joseph disease mouse models through SIRT1 pathway. Nature Communications 2016, 7:11445.

Ferreira-Marques M, Aveleira CA, Carmo-Silva S, Botelho M, Pereira de Almeida L and Cavadas C. Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation. Aging (Albany NY) 2016, 8:1470-1484.

Cavadas C, Aveleira C, Souza G, Velloso L. Defective proteostasis in the hypothalamus A relevant pathophysiological mechanism from obesity to ageing. Nature Reviews Endocrinology 2016, 2(12):723-733.

Aveleira CA, Botelho M, Carmo-Silva S, Pascoal JF, Ferreira-Marques M, Nóbrega, C, Cortes L, Valero J, Sousa-Ferreira L, Álvaro AR, Santana M, Kügler S, Pereira de Almeida L, Cavadas C. Neuropeptide Y stimulates autophagy in hypothalamic neurons. PNAS 2015, 112(13): E1642-E1651

Botelho M & Cavadas C. Neuropeptide Y: an anti-aging player? Trends in Neurosciences 2015, 38(11):701-11

Read more

Carmo-Silva S, Nobrega C, Pereira de Almeida L, Cavadas C. Unraveling the Role of Ataxin-2 in Metabolism. Trends Endocrinol Metab. 2017, 28(4):309-318.

Marques AP, Rosmaninho-Salgado J, Estrada M, Cortez V, Nobre RJ, Cavadas C. Hypoxia mimetic induces lipid accumulation through mitochondrial dysfunction and stimulates autophagy in murine preadipocyte cell line. Biochim Biophys Acta. 2017, 1861(3):673-682.

Duarte-Neves J, Pereira de Almeida L and Cavadas C. Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiol Dis. 2016, 95:210-224.

Duarte-Neves J, Gonçalves N, Cunha-Santos J, Simões AT, den Dunnen WF, Hirai H, Kügler S, Cavadas C*, Pereira de Almeida L*. Neuropeptide Y mitigates neuropathology and motor deficits in mouse models of Machado-Joseph disease. Hum Mol Genet. 2015, 24: 5451-5463.

Santana MM, Rosmaninho-Salgado J, Cortez V, Pereira FC, Kaster MP, Aveleira CA, Ferreira M, Álvaro AR, Cavadas C. Impaired adrenal medullary function in a mouse model of depression induced by unpredictable chronic stress. Eur Neuropsychopharmacol. 2015, 25(10):1753-66.

Aveleira CA, Botelho M, Cavadas C. NPY/neuropeptide Y enhances autophagy in the hypothalamus: a mechanism to delay aging? Autophagy 2015, 112(13):E1642-51.

Santos-Carvalho A, Ambrósio AF, Cavadas C. Neuropeptide Y system in the retina: From localization to function. Prog Retin Eye Res. 2015, 47:19-37.

Faria R, Santana MM,. Aveleira CA, Simões C, Maciel E, Melo M, Santinha D, Oliveira MM, Peixoto F, Domingues P, Cavadas C, M. Domingues RM. Alterations in phospholipidomic profile in brain of mouse model of depression induced by chronic unpredictable stress. Neuroscience, 2014, 273:1-11.

Sousa-Ferreira L, Aveleira C, Botelho M, Alvaro AR, Pereira de Almeida L, Cavadas C. Fluoxetine induces proliferation and inhibits differentiation of hypothalamic neuroprogenitor cells in vitro. PLoS One. 2014, 5;9(3):e88917.

Sousa-Ferreira L, Pereira de Almeida L, Cavadas C. Role of hypothalamic neurogenesis in feeding regulation. Trends Endocrinol Metab. 2014, 25(2):80-8.

Sousa-Ferreira L, Pereira de Almeida L, Cavadas C; “microRNAs and obesity”; chapter of the book “Molecular Mechanisms Underpinning the Development of Obesity”, Springer, 2014 (ISBN 978-3-319-12765-1)

Santos-Carvalho A, Álvaro AR, Martins J, Ambrósio AF, Cavadas C. Emerging novel roles of neuropeptide Y in the retina: from neuromodulation to neuroprotection. Prog Neurobiol. 2014, 112:70-9.

Santana MM, Ehrhart-Bornstein M, Cavadas C. Progenitor cells in chromospheres: in response to Arthur S. Tischler. Stem Cells Transl Med. 2013, 2(12):1020-1.

Santos-Carvalho, A R Álvaro, A F Ambrósio, C Cavadas Neuropeptide Y receptors activation protects rat retinal neural cells against necrotic and apoptotic cell death induced by glutamate. Cell Death and Disease 2013, 4, e636

Santos-Carvalho A, Aveleira CA, Elvas F, Ambrósio AF, Cavadas C. Neuropeptide Y Receptors Y1 and Y2 are Present in Neurons and Glial Cells in Rat Retinal Cells in Culture. Invest Ophthalmol Vis Sci. 2013, 17;54(1):429-43.

Vindeirinho J, Costa GN, Correia MB, Cavadas C, Santos PF. Effect of diabetes/hyperglycemia on the rat retinal adenosinergic system. PLoS One. 2013;8(6):e67499.

Santana MM, Chung KF, Vukicevic V, Rosmaninho-Salgado J, Kanczkowski W, Cortez V, Hackmann K, Bastos CA, Mota A, Schrock E, Bornstein SR, Cavadas C*, Ehrhart-Bornstein M*. Isolation, characterization, and differentiation of progenitor cells from human adult adrenal medulla. Stem Cells Transl Med. 2012, 1(11):783-91.

Rosmaninho-Salgado J, Cortez V, Estrada M, Santana MM, Gonçalves A, Marques AP, Cavadas C. Intracellular mechanisms coupled to NPY Y(2) and Y(5) receptor activation and lipid accumulation in murine adipocytes. Neuropeptides 2012, S0143-4179.

Rosmaninho-Salgado J, Marques AP, Estrada M, Santana M, Cortez V, Grouzmann E, Cavadas C. Dipeptidyl-peptidase-IV by cleaving neuropeptide Y induces lipid accumulation and PPAR-γ expression. Peptides 2012, 37(1):49-54.

Cortez V, Santana M, Marques P, Mota A, Rosmaninho-Salgado J, Cavadas C. Regulation of catecholamine release in human adrenal chromaffin cells by ß-adrenoceptors. Neurochem Int. 2012, 60: 387-393.

Martins J, Castelo-Branco M, Oliveiros B, Fernandes E, Carvalho F, Cavadas C and Ambrósio AF - Effects of 3,4-methylenedioxymethamphetamine administration on retinal physiology in the rat. PLoS One 2012, 6(12): e29583.

Costa GN, Vindeirinho J, Cavadas C, Ambrósio AF, Santos PF. Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose. Mol Cell Neurosci. 2012, 50 : 113–123

Sousa-Ferreira L, Garrido M, Nascimento-Ferreira I, Nobrega C, Santos-Carvalho A, Álvaro AR, Rosmaninho-Salgado J, Kaster M, Kügler S, Pereira de Almeida L, Cavadas C. Moderate long-term modulation of Neuropeptide Y in the Arcuate Nucleus induces energy balance alterations in adult rats. PLoS One, 2011 6(7):e22333

Sousa-Ferreira L, Álvaro AR, Aveleira C, Santana M, Brandão I, Kügler S, Pereira de Almeida L, Cavadas C. Proliferative hypothalamic neurospheres express NPY, AGRP, POMC, CART and Orexin-A and differentiate to functional neurons expressing appetite-related neuropeptides. PLoS One 2011, 6(5):e19745

Alvaro AR, Rosmaninho-Salgado J, Ambrósio AF, Cavadas C.- Neuropeptide Y inhibits [Ca(2+)](i) changes in rat retinal neurons through NPY Y(1),Y(4), Y(5) receptors. J Neurochem. 2009, 109:1508-1515.

Rosmaninho-Salgado J, Araújo IM, Alvaro AR, Mendes AF, Ferreira L, Grouzmann E, Mota A, Duarte EP, Cavadas C. - Regulation of catecholamine release and tyrosine hydroxylase in human adrenal chromaffin cells by interleukin-1beta: role of neuropeptide Y and nitric oxide. J Neurochem. 2009, 109: 911-22.

Ruohonen ST, Savontaus E, Rinne P, Rosmaninho-Salgado J, Cavadas C, Ruskoaho H, Koulu M, Pesonen U. Stress-Induced Hypertension and Increased Sympathetic Activity in Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons. Neuroendocrinology 2009, 89:351-60.

Book Chapter; Title “Neuropeptide Y family peptides” by Cláudia Cavadas, Joana Rosmaninho- Salgado, Eric Grouzmann; Book Title: “Bioactive peptides”; edited by John Howl, Sarah Jones. Boca Raton, FL : CRC Press, 2009. ISBN 9781420061147

Xapelli S, Bernardino L, Ferreira R, Grade S, Silva AP, Salgado JR, Cavadas C, Grouzmann E, Poulsen FR, Jakobsen B, Oliveira CR, Zimmer J, Malva JO. Interaction between neuropeptide Y (NPY) and brain-derived neurotrophic factor in NPY-mediated neuroprotection against excitotoxicity: a role for microglia. Eur J Neurosci. 2008, 27:2089-102.

Alvaro AR, Martins J, Araújo IM, Rosmaninho-Salgado J, Ambrósio AF, Cavadas C. - Neuropeptide Y stimulates retinal neural cell proliferation - involvement of nitric oxide. J Neurochem. 2008, 105, 2501-2510.

Alvaro AR, Martins J, Costa AC, Fernandes E, Carvalho F, Ambrósio AF, Cavadas C. - Neuropeptide Y protects retinal neural cells against cell death induced by ecstasy. Neuroscience 2008, 152:97-105.

Rosmaninho-Salgado J, Araújo IM, Alvaro AR, Duarte EP, Cavadas C. Intracellular signaling mechanisms mediating catecholamine release upon activation of NPY Y1 receptors in mouse chromaffin cells. J Neurochem. 2007, 103(3):896-903.

Alvaro AR, Rosmaninho-Salgado J, Santiago AR, Martins J, Aveleira C, Santos PF, Pereira T, Gouveia D, Carvalho AL, Grouzmann E, Ambrósio AF, Cavadas C. NPY in rat retina is present in neurons, in endothelial cells and also in microglial and Müller cells. Neurochem Int. 2007, 50:757-63.

Cavadas C, Waeber B, Pedrazzini T, Grand D, Aubert JF, Buclin T, Grouzmann E. NPY Y1 receptor is not involved in the hemodynamic response to an acute cold pressor test in mice. Peptides 2007, 28(2):315-9

Rosmaninho-Salgado J, Alvaro AR, Grouzmann E, Duarte EP, Cavadas C. Neuropeptide Y regulates catecholamine release evoked by interleukin-1beta in mouse chromaffin cells. Peptides 2007, 28(2):310-4.

Cavadas C, Céfai D, Rosmaninho-Salgado J, Vieira-Coelho MA, Moura E, Busso N, Pedrazzini T, Grand D, Rotman S, Waeber B, Aubert JF, Grouzmann E. Deletion of the neuropeptide Y (NPY) Y1 receptor gene reveals a regulatory role of NPY on catecholamine synthesis and secretion. PNAS USA 20

GROUP LEADER

Cláudia Cavadas

Assistant Professor
Faculty of Pharmacy
University of Coimbra

Ph: +351 963928766

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Financiado por Fundos FEDER através do Programa Operacional Factores de Competitividade – COMPETE 2020 e por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia no âmbito do projecto Estratégico com referência atribuida pelo COMPETE: POCI-01-0145-FEDER-007440