Professor Daniela Riccardi

Emeritus Professor

: riccardi@cardiff.ac.uk

: Available for postgraduate supervision

The ability of cells to monitor changes in the environment is crucial to life. In humans, excessive exposure to certain noxious external cues can result in a variety of life-threatening diseases such as asthma, smoker’s cough (COPD) and scarring of the lung (pulmonary fibrosis). Previously in my laboratory we have discovered the existence of “sensors” throughout our body. Currently we are investigating: i) The ability of noxious stimuli such as smoke and urban particulate matter to activate these sensors; ii) The consequences of aberrant activation of these sensors at the molecular, cellular and whole organism level; iii) The possibility to use new and existing drugs targeting these sensors to specifically prevent currently incurable inflammatory lung disease.

Useful links

Development of inhaled CaSR antagonists, calcilytics, for asthma:

https://www.youtube.com/watch?v=jIqz46r9thU&feature=youtu.be

Calcilytics as novel therapeutics for pulmonary fibrosis:

https://www.medrxiv.org/content/10.1101/2020.03.12.20034751v1

I obtained my BA in Zoology and MRes in Physiopathological methods from the University of Milan, Italy, where I investigated mechanisms of fluid transport across mammalian epithelia. I did my PhD in Physiology working between the University of Milan and the Harvard Medical School, Boston, MA, USA, under the supervision of Prof. SC Hebert, in the Renal Division of the Brigham and Women's Hospital. There, in 1993 we identified the first G protein-coupled receptor for an ion, calcium. The paper describing the cloning of the Calcium-Sensing Receptor, CaSR, from parathyroid glands is now a "citation classic" with >2,000 citations. While in Prof Hebert lab, I was awarded a Research Fellowship from the National Kidney Foundation to identify the renal CaSR. The parathyroid and kidney CaR are the target for a novel class of small molecule drugs, the calcimimetics, which were developed for the treatment of chronic kidney disease. In 2004, calcimimetics were the first G protein-coupled receptor allosteric modulators to enter the market and in 2014 calcimimetics were within the top 100 most sold drugs. In 1997, I moved to the UK where I established my independent research group at Manchester University and in 2004 I moved to Cardiff University as a Reader, then Professor (2012) within the School of Biosciences. Currently my group is actively pursuing the development of CaSR-based therapeutics for the treatment of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis.

Honours and awards

2002 - John Haddad Young Investigator Award (AIMM/ASBMR)
2000 - The Wellcome Trust Prize for Excellence in Physiology
1995 - First Prize, Excellence in Research (ASN/NKF)

Professional memberships

2018 - European Respiratory Society
2018 - Welsh Thoracic Society
1997 - Physiological Society

Academic positions

2015 - present: Deputy Head of School
2004 - present: Reader and Professor, Cardiff University
1997 - 2004: Lecturer and Senior Lecturer, University of Manchester, UK
1993 - 1997: Research Fellow, renal Division, Harvard Medical School, Boston, MA USA

Speaking engagements

Asthma UK Day: the opportunity of asthma research in Wales (2017)

Committees and reviewing

Journal reviewer (e.g., Nature, PNAS, JCI, Science TM, Scientific Reports...)
Physiological Society Council (2012-2016)
BBSRC pool of experts (2015-2017)

2009

Wilkinson, W. J.et al. 2009. Carbon monoxide is a rapid modulator of recombinant and native P2X(2) ligand-gated ion channels. British Journal of Pharmacology 158(3), pp. 862-871. (10.1111/j.1476-5381.2009.00354.x)
Kemp, P. J.et al. 2009. Enzyme-linked oxygen sensing by potassium channels. Annals of the New York Academy of Sciences 1177, pp. 112-118. (10.1111/j.1749-6632.2009.05025.x)
Topala, C.et al. 2009. Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5. Cell Calcium 45(4), pp. 331-339. (10.1016/j.ceca.2008.12.003)
Brazier, S. P.et al. 2009. Cysteine residues in the C-terminal tail of the human BKCaα subunit are important for channel sensitivity to carbon monoxide. Presented at: International Society of Arterial Chemoreception. 17th Meeting, Valladolid, Spain, 1-5 July 2008Arterial Chemoreceptors. Advances in Experimental Medicine and Biology Vol. 648. Netherlands: Springer Netherlands pp. 49-56., (10.1007/978-90-481-2259-2_5)
Alam, M.et al. 2009. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovascular Research 81(2), pp. 260-268. (10.1093/cvr/cvn279)
Topala, C.et al. 2009. Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5. Cell Calcium 45(4), pp. 331-339.
Riccardi, D.et al. 2009. Novel regulatory aspects of the extracellular Ca2+-sensing receptor, CaR. Pflugers Archiv-European Journal of Physiology 458(6), pp. 1007-1022. (10.1007/s00424-009-0681-z)
De Proost, I.et al. 2009. Purinergic signaling in the pulmonary neuroepithelial body microenvironment unraveled by live cell imaging. The FASEB Journal 23(4), pp. 1153-1160. (10.1096/fj.08-109579)
Telezhin, V.et al. 2009. Hydrogen Sulfide inhibits human BKCa channels. Advances in Experimental Medicine and Biology 648, pp. 65-72. (10.1007/978-90-481-2259-2_7)
Cayzac, S.et al. 2009. Effects of the polyamine spermine on arterial chemoreception. Presented at: International Society of Arterial Chemoreception. 17th Meeting, Valladolid, Spain, 1-5 July 2008 Presented at Gonzalez, C., Nurse, C. A. and Peers, C. eds.Arterial chemoreceptors. Advances in Experimental Medicine and Biology Vol. 648. Netherlands: Springer Netherlands pp. 97-104., (10.1007/978-90-481-2259-2_11)

2008

Finney, B.et al. 2008. Regulation of mouse lung development by the extracellular calcium-sensing receptor, CaR. Journal of Physiology 586(24), pp. 6007-6019. (10.1113/jphysiol.2008.161687)
De Proost, I.et al. 2008. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment. American Journal of Respiratory Cell and Molecular Biology 39(2), pp. 180-189. (10.1165/rcmb.2008-0011OC)
Williams, S. E.et al. 2008. A structural motif in the C-terminal tail of slo1 confers carbon monoxide sensitivity to human BKCa channels. Pflugers Archiv-European Journal of Physiology 456(3), pp. 561-572. (10.1007/s00424-007-0439-4)
Vizard, T. N.et al. 2008. Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nature Neuroscience 11(3), pp. 285-291. (10.1038/nn2044)
Gibbons, C. E.et al. 2008. Calcium-sensing receptor antagonism or lithium treatment ameliorates aminoglycoside-induced cell death in renal epithelial cells. Biochimica et Biophysica Acta - Molecular Basis of Disease 1782(3), pp. 188-195. (10.1016/j.bbadis.2008.01.003)
Riccardi, D. and Martin, D. 2008. The role of the calcium-sensing receptor in the pathophysiology of secondary hyperparathyroidism. NDT Plus 1(Suppl.), pp. i7-i11. (10.1093/ndtplus/sfm038)
Timmermans, J. P.et al. 2008. Expression of P2X receptors in LAD-2 cells and human lung mast cells [Abstract]. Purinergic Signalling 4(S1), pp. S159. (10.1007/s11302-008-9116-0)
Wilkinson, W. J.et al. 2008. Carbon monoxide is a rapid modulator of recombinant and native P2X2 ligand-gated ion channels [Abstract]. Purinergic Signalling 4(S1), pp. 26. (10.1007/s11302-008-9116-0)
Gamba, G. and Riccardi, D. 2008. Cell biology of thiazide bone effects. Presented at: 2nd International Urolithiasis Research Symposium, Indianapolis, IN, USA, 17-18 April 2008 Presented at Evan, A. P. et al. eds.Renal Stone Disease 2: 2nd International Urolithiasis Research Symposium, Indianapolis, Indiana, 17-18 April 2008. AIP Conference Proceedings Vol. 1049. New York: American Institute of Physics pp. 44-52., (10.1063/1.2998060)

2007

Dvorak, M. M.et al. 2007. Thiazide Diuretics Directly Induce Osteoblast Differentiation and Mineralized Nodule Formation by Interacting with a Sodium Chloride Co-Transporter in Bone. Journal of the American Society of Nephrology 18(9), pp. 2509-2516. (10.1681/ASN.2007030348)
Lu, W.et al. 2007. Seasonal changes in peptide, receptor and ion channel mRNA expression in the caudal neurosecretory system of the European flounder (Platichthys flesus). General and Comparative Endocrinology 153(1-3), pp. 262-272. (10.1016/j.ygcen.2007.05.004)

2006

Lu, W.et al. 2006. Molecular characterization and expression of Urotensin II and its receptor in the flounder (Platichthys flesus): A hormone system supporting body fluid homeostasis in euryhaline fish. Endocrinology 147(8), pp. 3692-3708. (10.1210/en.2005-1457)
Kemp, P. J.et al. 2006. Functional proteomics of BK potassium channels: Defining the acute oxygen sensor. In: Chadwick, D. J. and Goode, J. eds. Signalling Pathways in Acute Oxygen Sensing: Novartis Foundation Symposium 272. Novartis Foundation Symposia Wiley-Blackwell, pp. 141-151., (10.1002/9780470035009.ch12)
Kemp, P. J.et al. 2006. In search of the acute oxygen sensor: Functional proteomics and acute regulation of large-conductance, calcium-activated potassium channels by hemeoxygenase-2. In: Hayashida, Y., Gonzalez, C. and Kondo, H. eds. The Arterial Chemoreceptors., Vol. 580. Advances in Experimental Medicine and Biology Springer, pp. 137-146., (10.1007/0-387-31311-7_21)
Kemp, P. J.et al. 2006. General discussion II. Novartis Foundation Symposium(272), pp. 131-140.

2005

Ward, D. T.et al. 2005. Aminoglycosides induce acute cell signaling and chronic cell death in renal cells that express the calcium-sensing receptor. Journal of the American Society of Nephrology 16(5), pp. 1236-1244. (10.1681/ASN.2004080631)
Ward, D. T.et al. 2005. Altered expression of iron transport proteins in streptozotocin-induced diabetic rat kidney. Biochimica et Biophysica Acta - Molecular Basis of Disease 1740(1), pp. 79-84. (10.1016/j.bbadis.2005.01.008)
Maldonado-Perez, D. and Riccardi, D. 2005. The calcium-sensing receptor as a nutrient sensor [RETRACTED]. Biochemical Society Transactions 33(1), pp. 316-320. (10.1042/BST0330316)

2004

Williams, S. E. J.et al. 2004. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science, pp. 2993-2997. (10.1126/science.1105010)
Dvorak, M. M.et al. 2004. Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones.. Proceedings of the National Academy of Sciences of the USA 101(14), pp. 5140-5145. (10.1073/pnas.0306141101)
Lu, W.et al. 2004. Coexpression of corticotropin-releasing hormone and urotensin I precursor genes in the caudal neurosecretory system of the Euryhaline flounder (Platichthys flesus): A possible shared role in peripheral regulation. Endocrinology 145(12), pp. 5786-5797. (10.1210/en.2004-0144)
Procino, G.et al. 2004. Extracellular calcium antagonizes forskolin-induced aquaporin 2 trafficking in collecting duct cells. Kidney International 66(6), pp. 2245-2255. (10.1111/j.1523-1755.2004.66036.x)
Brierley, M. J.et al. 2004. Voltage- and Ca2+-dependent burst generation in neuroendocrine dahlgren cells in the teleost platichthys flesus. Journal of Neuroendocrinology 16(10), pp. 832-841. (10.1111/j.1365-2826.2004.01238.x)
Moreno, E.et al. 2004. A single nucleotide polymorphism alters the activity of the renal Na+:Cl- cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity. Journal of Biological Chemistry 279(16), pp. 16553-16560. (10.1074/jbc.M400602200)
Dvorak, M. M. and Riccardi, D. 2004. Ca2+ as an extracellular signal in bone. Cell Calcium 35(3), pp. 249-255. (10.1016/j.ceca.2003.10.014)
Riccardi, D. 2004. The role of extracellular calcium in the regulation of intracellular calcium and cell function (II). Some answers and more questions. Cell Calcium 35(3), pp. 179-181. (10.1016/j.ceca.2003.10.007)

2003

Maldonado-Pérez, D.et al. 2003. Human calcium-sensing receptor can be suppressed by antisense sequences. Biochemical and Biophysical Research Communications 311(3), pp. 610-617. (10.1016/j.bbrc.2003.10.041)
Brierley, M. J.et al. 2003. Electrical activity of caudal neurosecretory neurons in seawater- and freshwater-adapted flounder: responses to cholinergic agonists. Journal of Experimental Biology 206(22), pp. 4011-4020. (10.1242/jeb.00631)
Ferguson, C. J.et al. 2003. Iron handling and gene expression of the divalent metal transporter, DMT1, in the kidney of the anemic Belgrade (b) rat. Kidney International 64(5), pp. 1755-1764. (10.1046/j.1523-1755.2003.00274.x)
Wareing, M.et al. 2003. Altered dietary iron intake is a strong modulator of renal DMT1 expression. American Journal of Physiology-Renal Physiology 285(6), pp. F1050-F1059. (10.1152/ajprenal.00064.2003)

2002

Riccardi, D. 2002. Wellcome prize lecture cell surface, ion-sensing receptors. Experimental Physiology 87(4), pp. 403-411. (10.1111/j.1469-445X.2002.tb00053.x)
Ward, D. T., McLarnon, S. J. and Riccardi, D. 2002. Aminoglycosides increase intracellular calcium levels and ERK activity in proximal tubular OK cells expressing the extracellular calcium-sensing receptor. Journal of the American Society of Nephrology, pp. 1481-1489. (10.1097/01.ASN.0000015623.73739.B8)
McLarnon, S. J.et al. 2002. Aminoglycoside antibiotics induce pH-sensitive activation of the calcium-sensing receptor. Biochemical and Biophysical Research Communications 297(1), pp. 71-77. (10.1016/S0006-291X(02)02133-2)
Konstas, A. A.et al. 2002. Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein. Journal of Biological Chemistry 277(33), pp. 29406-29416. (10.1074/jbc.M203018200)
McLarnon, S. J. and Riccardi, D. 2002. Physiological and pharmacological agonists of the extracellular Ca2+-sensing receptor. European Journal of Pharmacology 447(2-3), pp. 271-278. (10.1016/S0014-2999(02)01849-6)
Ward, D. and Riccardi, D. 2002. Renal physiology of the extracellular calcium-sensing receptor. Pflugers Archiv European Journal of Physiology 445(2), pp. 169-176. (10.1007/s00424-002-0914-x)

2001

Ferguson, C. J.et al. 2001. Cellular localization of divalent metal transporter DMT-1 in rat kidney. American Journal of Physiology-Renal Physiology 280(5), pp. F803-F814.
Ward, D. T.et al. 2001. Functional, molecular, and biochemical characterization of streptozotocin-induced diabetes. Journal of the American Society of Nephrology 12(4), pp. 779-790.

2000

Wareing, M.et al. 2000. In vivo characterization of renal iron transport in the anaesthetized rat. The Journal of Physiology 524(2), pp. 581-586. (10.1111/j.1469-7793.2000.00581.x)
Riccardi, D.et al. 2000. Dietary phosphate and parathyroid hormone alter the expression of the calcium-sensing receptor (CaR) and the Na + -dependent P i transporter (NaPi-2) in the rat proximal tubule. Pflugers Archiv European Journal of Physiology 441(2-3), pp. 379-387. (10.1007/s004240000436)
Riccardi, D. 2000. Calcium ions as extracellular, first messengers. Zeitschrift fur Kardiologie -Supplement- 89(Supp 2), pp. 9-14.

Module contributor: BI2331 Physiology
Module contributor: BI3355 Advances in Physiology and Pathophysiology

Research goal: to develop CaSR antagonists, calcilytics, as novel therapeutics for pulmonary diseases such as asthma, COPD and pulmonary fibrosis

Asthma remains incurable, a major and increasing cause of global suffering and premature death and affects 340 million people worldwide. Current standard asthma therapy is palliative and 5-10% of asthma sufferers do not respond to any treatment at all. What is needed is a new approach to asthma therapy which is safe, that targets the underlying cause of the disease and that prevents environmentally-induced asthma exacerbations. During asthma, the expression of certain polycations such as eosinophil cationic protein, major basic protein, spermine and spermidine) and of polyamines such as poly-L-arginine is increased. We have made the discovery that the CaSR is expressed in the airways, where activation of this receptor by polycations and polyamines drives airways hyperreactivity, bronchoconstriction and inflammation in allergic asthma (Figure 1). Excitingly, blocking the CaSR using calcilytics, we could prevent all of these effects (Yarova et al, 2015). Recently we have also shown that inhaled calcilytics suppress inflammation as well as the current standard-of-care, inhaled corticosteroids, but they also suppress airway hyperresponsiveness and remodelling while corticosteroids do not (Yarova et al, JPET 2020)(Figure 2).

Recently my laboratory has also made the discovery that the CaSR can also be activated by chemicals contained in cigarette smoke and car fumes, and by urban particulate matter (Mansfield et al, 2019)(Figure 3), strongly implicating the CaSR in the development of currently untreatable diseases such as COPD (smoker’s cough) and idiopathic pulmonary fibrosis (Wolffs et al, 2020).

Oral calcilytics were initially developed as an anti-osteoporosis drug. While they were safe and well-tolerated in patients, their development was terminated due to lack of efficacy for this indication. Our goal is repurpose existing calcilytics, delivered topically to the lung, as novel therapeutics to treat inflammatory lung disorders in people. In addition, in collaboration with Prof Andrea Brancale (Cardiff School of Pharmacy), we are also developing entirely novel calcilytics with an optimal lung delivery profile for the treatment of lung disease.

Patent: WO2014049351 Calcium/cation-sensing receptor (casr) antagonist like nps89636 for use in treating inflammatory lung disorders (asthma or copd)

References:

Yarova et al. Sci Trans Med 284, ra60, 2015 (doi: 10.1126/scitranslmed.aaa0282)
Yarova et al., JPET 2020 (DOI: https://doi.org/10.1124/jpet.120.000281
Mansfield et al.,Eur Resp J 2019; 54: Suppl. 63, PA2401
Wolffs et al: https://www.medrxiv.org/content/10.1101/2020.03.12.20034751v1
https://patents.google.com/patent/WO2014049351A1/en

Collaborators

National

Profs A Brancale, K Broadley, B Hope-Gill, G Taylor, Drs EJ Kidd, WR Ford, B Kariuki, (Cardiff);
Prof K Lewis (Swansea University and Respiratory Innovation Wales);
Prof L Mur (Aberystwyth University);
Profs CJ Corrigan, JPT Ward, C Page and C Hawrylowicz (King's College London)
Prof D Thickett (Birmingham University)
Dr DT Ward (Manchester University)

International

Prof E Kallay, Dr M Schepelmann (Vienna University)
Dr I Ellinger, R Ecker (TissueGnostics, Vienna)
Dr W Chang (UCSF, USA)
Prof G Gamba, Mexico City (UNAM)
Prof YS Prakash and C Pabelick (Mayo Clinic, Rochester, USA)
Dr M Ranieri, Prof G Valenti (University of Bari, Italy)
Prof S Ying (CMU, China)

Work funded by

Asthma UK, King's Commercialisation Institute, The Live Sciences Research Network, Marie Curie ITN “Multifaceted CaSR” and Marie Curie ETN “CaSR Biomedicine", KESS2 studentship, the Saunders Legacy Research Fund

Active research grants

Marie Curie ETN "Biomedicine"
KESS2 studentship

Role of the calcium-sensing recepto in inflammatory lung disease
Novel therapies for asthma, chronic obstructve pulmonary disease and pulmonary fibrosis
Mechanisms of pathological vascular calcification
Calcium-sensing receptor-based therapeutics for pulmonary disease

Past projects

All my PhD students have graduated successfully and on time. Here is a list of PhD students I have supervised in the last 5 years:

Main supervisor :

Ping Huang - (Marie Cure ETN "CaSR Biomedicine" - Developing CaSR-based therapeutics, calcilytics, for steroid-resistant asthma (2016-2019)
Bethan Mansfield (KESS2 PhD student) - Development of calcilytics for inflammatory lung disease (2018-current)
Kasope Wolffs - Role of the calcium-sensing receptor in the development of pulmonary fibrosis (2017-current)
Richard Bruce - Role of the calcium-sensing receptor in pulmonary remodelling (2017-current)
Petar Popov (Masters student)

Professor Daniela Riccardi

Overview

Useful links

Biography

Honours and awards

Professional memberships

Academic positions

Speaking engagements

Committees and reviewing

Publications

2021

2020

2019

2018

2017

2016

2015

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2012

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Articles

Book sections

Conferences

Teaching

References:

Collaborators

National

International

Work funded by

Active research grants

Supervision

Past projects

Areas of expertise

Related news

Researchers’ “hugely exciting” asthma discovery

External profiles