Contact
I have a complex scientific background that encompasses everything from molecular biology (as little as possible in the DNA sense) to ecology. This is mainly due to training as a biochemist before moving on to pharmacology while being an avid amateur Natural Historian. As a Biochemist I am allowed to have wide and varied interests and I take full advantage of this as the biochemistry of most organisms is basically similar. If I were intelligent enough I would be a polymath but I am happy to be a jack of all trades and some of my interests are below although I hate limiting or categorizing my research........
I have a complex scientific background that encompasses everything from molecular biology (as little as possible in the DNA sense) to ecology. This is mainly due to training as a biochemist before moving on to pharmacology while being an avid amateur Natural Historian. As a Biochemist I am allowed to have wide and varied interests and I take full advantage of this as the biochemistry of most organisms is basically similar. If I were intelligent enough I would be a polymath but I am happy to be a jack of all trades and some of my interests are below although I hate limiting or categorizing my research........
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| NADP+ |
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| NAD+ |
Pyridine nucleotides
The pyridine nucleotides NAD(P) are well known co-enzymes that participate in many reactions of basic metabolism in cells. Recent advances suggest that they also play signalling roles and are involved in pharmacologically more attractive processes such as gene expression, DNA repair, calcium signalling and receptor activation. These new roles for NAD(P) have led to the homeostasis mechanisms for NAD(P) being identified as potential drug targets. The lab bases most of its research around elucidating NAD(P) homeostasis mechanisms in various disease models and potential therapeutic strategies related to NAD(P) homeostasis.
Quite a lot of the work we do seems to revolve around the protein CD38. This protein is a classic cell-cell adhesion receptor (binding to CD31) but is also an ectoenzyme. As an enzyme, it is capable of performing three distinct enzymatic reactions starting from NAD or NADP producing a number of products (e.g the second messengers cADPR and NAADP) but its main role may well be in NAD homeostasis.
Current Projects (Human Biology):
The role of the enzymatic activity of CD38 in CLL (chronic lymphocytic leukaemia)
CD38 is a well characteried marker for CLL with increased expression being linked to a more aggressive cancer. The receptor functions of CD38 have been shown to play a role in this pathophysiology as CD38, when stimulated by binding to CD31, mediates cell proliferation. As CD38 is also an (ecto)enzyme capable of degrading NAD(P), we are interested in how increased CD38 expression might affect NAD(P) levels and NAD(P) dependent processes.
PhD student - Zainab Al-Abady
FK866 as a chemotherapeutic drug
FK866 is a small molecule inhibitor of NMPRTase, a key enzyme in NAD recycling. Treatment of cells with FK866 leads to drastic decreases in NAD levels in cells due to NAD consumption via mechanisms such as PARP. Currently we are trying to characterise the precise mechanisms by which FK866-induced NAD depletion occurs. We are also looking at various disease models to see whether FK866 might be a viable co-chemotherapy agent able to potentiate the effects of conventional chemotherapy agents.
PhD student - Niketa Ferguson
Current Projects (Human Biology):
The role of the enzymatic activity of CD38 in CLL (chronic lymphocytic leukaemia)
CD38 is a well characteried marker for CLL with increased expression being linked to a more aggressive cancer. The receptor functions of CD38 have been shown to play a role in this pathophysiology as CD38, when stimulated by binding to CD31, mediates cell proliferation. As CD38 is also an (ecto)enzyme capable of degrading NAD(P), we are interested in how increased CD38 expression might affect NAD(P) levels and NAD(P) dependent processes.
PhD student - Zainab Al-Abady
FK866 as a chemotherapeutic drug
FK866 is a small molecule inhibitor of NMPRTase, a key enzyme in NAD recycling. Treatment of cells with FK866 leads to drastic decreases in NAD levels in cells due to NAD consumption via mechanisms such as PARP. Currently we are trying to characterise the precise mechanisms by which FK866-induced NAD depletion occurs. We are also looking at various disease models to see whether FK866 might be a viable co-chemotherapy agent able to potentiate the effects of conventional chemotherapy agents.
PhD student - Niketa Ferguson
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| FK866 |
NAD homeostasis pathways and immune modulation
A number of recent reports have implicated various steps in the NAD synthesis and recycling pathways as playing a role in the function of a variety of immune cells. Classic amongst these pathways is the role of the enzyme IDO (and its product kyneurenine) in modulation of immune function. The project aims to both elucidate the pathways by which NAD homeostasis acts to modulate immune function and to identify any potential treatment strategies that could be used.Sounds wonderfully vague and that is exactly what it is at the moment. We'll see where it goes! Expertise in the dark arts (immunology) provided by co-supervisor Dr Andrew Foey.
PhD student - Abbas Al-Shabany
Current Projects (Biological):
Mycotoxins
Fusarium head blight is a common fungal disease on wheat and barley particularly relevant in the soggy south west! Fusarium spp. produce a toxin known affectionately as Vomitoxin (more scientifically Deoxynivalenol; DON) that can persist through grain storage leading to the potential for toxic effects of DON in animal (and human) feeds. This project is aimed at characterising the stability of DON under various conditions of grain storage and in the presence of various other microorganisms.
PhD student - Will Vevers
Genetic diversity and "fitness" in Bombus spp.
Bumblebees are currently under significant pressures, both anthropogenic and not. Some of the rarer species have also become genetically isolated from other populations (apparently). This project is aimed at measuring a number of "fitness" characteristics in isolated and widespread species. I am a co-supervisor (with Mairi Knight and John Ellis) on this project supplying technical support for biochemical assays.
PhD student - Sarah Rustage
Causes of rarity
Very few species are common and widespread and most are geographically isolated. While the concept of species occupying a particular niche can go some way to explain this, the definition of niche often refers to some behavioural characteristic. Behind everything there must be some kind of molecular reason! Looking at species pairs of Diving Beetles where one sister species is common and widespread while the other is range restricted, we are measuring a number of metabolic and immunocompetence parameters to see if these are behind the differences. Just a co-supervisor on this one with the metabolism guru John Moody and Diving Beetle uberguru Dave Bilton.
PhD student - Bekah Simpson
Other stuff
My ideal job would have been as a 17th century Natural Historian but there is little demand for this these days unfortunately. I can get interested in just about anything biological and am particularly interested in identification. Current groups of interest include plants, Lepidoptera, Odonata, Isopods, terrestrial crustaceans, birds, mammals......... you're getting the idea!
Other stuff
My ideal job would have been as a 17th century Natural Historian but there is little demand for this these days unfortunately. I can get interested in just about anything biological and am particularly interested in identification. Current groups of interest include plants, Lepidoptera, Odonata, Isopods, terrestrial crustaceans, birds, mammals......... you're getting the idea!
Publications
Almzaiel AJ, Billington R, Smerdon G, Moody AJ.Effects of hyperbaric oxygen treatment on antimicrobial function and apoptosis of differentiated HL-60 (neutrophil-like) cells. Life Sci. 2013 In Press
Almzaiel AJ, Billington R, Smerdon G, Moody AJ.Effects of hyperbaric oxygen treatment on antimicrobial function and apoptosis of differentiated HL-60 (neutrophil-like) cells. Life Sci. 2013 In Press
Hawar S, Vevers W, Karieb S, Ali BK, Billington R, Beal J. Biotransformation of patulin to hydroascladiol by Lactobacillus plantarum. Food Control (2013) In Press.
http://dx.doi.org/10.1016/j.foodcont.2013.05.023
http://dx.doi.org/10.1016/j.foodcont.2013.05.023
Almzaiel AJ, Billington R, Smerdon G, Moody AJ. Effects of hyperbaric oxygen treatment on antimicrobial function and apoptosis of differentiated HL-60 (neutrophil-like) cells. Life Sci. (2013) Jun 13. doi:pii: S0024-3205(13)00319-6. 10.1016/j.lfs.2013.06.003. [Epub ahead of print] PMID:23770209
Plattner H, Sehring IM, Mohamed IK, Miranda K, De Souza W, Billington R, Genazzani A, Ladenburger EM. Calcium signaling in closely related protozoan groups (Alveolata): Non-parasitic ciliates (Paramecium, Tetrahymena) vs. parasitic Apicomplexa (Plasmodium, Toxoplasma). Cell Calcium. (2012) 51(5):351-82.
Conforti L, Wilbrey A, Morreale G, Janeckova L, Beirowski B, Adalbert R, Mazzola F, Di Stefano M, Hartley R, Babetto E, Smith T, Gilley J, Billington RA, Genazzani AA, Ribchester RR, Magni G, Coleman M.Wld S protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. J Cell Biol. (2009) 184(4):491-500.
Genazzani AA, Billington RA. [Pharmacokinetic and pharmacodynamic features of palonosetron]. Tumori. (2008) 94(2):suppl 6-13. Review.
Gambara G, Billington RA, Debidda M, D'Alessio A, Palombi F, Ziparo E, Genazzani AA, Filippini A. NAADP-induced Ca2+ signaling in response to endothelin is via the receptor subtype B and requires the integrity of lipid rafts/caveolae. J Cell Physiol. (2008) 216(2):396-404.
Galli U, Ercolano E, Carraro L, Blasi Roman CR, Sorba G, Canonico PL, Genazzani AA, Tron GC, Billington RA. Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage. ChemMedChem. (2008) 3(5):771-9.
Billington RA, Genazzani AA, Travelli C, Condorelli F. NAD depletion by FK866 induces autophagy. Autophagy. (2008) 4(3):385-7.
Billington RA, Travelli C, Ercolano E, Galli U, Roman CB, Grolla AA, Canonico PL, Condorelli F, Genazzani AA. Characterization of NAD uptake in mammalian cells. J Biol Chem. (2008) 283(10):6367-74.
Tron GC, Pirali T, Billington RA, Canonico PL, Sorba G, Genazzani AA. Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med Res Rev. (2008) 28(2):278-308. Review.
Deaglio S, Vaisitti T, Billington RA, Bergui L, Omede' P, Genazzani AA, Malavasi F. CD38/CD19: a lipid raft-dependent signaling complex in human B cells. Blood. (2007) 109 (12), 5390-8.
Pirali T, Gatti S, Di Brisco R, Tacchi S, Zaninetti R, Brunelli E, Massarotti A, Sorba G, Canonico PL, Moro L, Genazzani AA, Tron GC, Billington RA. Estrogenic Analogues Synthesized by Click Chemistry. Chem. Med. Chem. (2007) 2 (4), 437-40.
Billington RA, Genazzani AA. PPADS is a reversible competitive antagonist of the NAADP receptor. Cell Calcium (2007) 41(6), 505-511.
Billington RA, Bruzzone S, De Flora A, Genazzani AA, Koch-Nolte F, Ziegler M, Zocchi E. Emerging functions of extracellular pyridine nucleotides. Mol. Med. (2006) 12(11-12), 324-7.
Billington RA, Harper C, Bellomo EA, Publicover S, Barratt CLR, Genazzani AA, Characterization of cADPR levels in human spermatozoa. Fertility and Sterility (2006) 86(4), 891-8.
Moccia F, Billington RA, Santella L. Pharmacological characterization of NAADP-induced Ca2+ signals in starfish oocytes. Biochem Biophys Res Commun. (2006) 348, 329-36.
Billington RA, Bellomo EA, Floriddia EM, Erriquez J, Distasi C, Genazzani AA. A transport mechanism for NAADP in a rat basophilic cell line. Faseb J. (2006) 20 (3), 521-3.
Floriddia EM, Pace D, Genazzani AA, Canonico PL, Condorelli F, Billington RA. Sphingosine releases Ca2+ from intracellular stores via the ryanodine receptor in sea urchin egg homogenates. Biochem Biophys Res Commun. (2005) 338 (3), 1316-21.
Appendino G, Prosperini S, Valdivia C, Ballero M, Colombano G, Billington RA, Genazzani AA, Sterner O. SERCA-inhibiting activity of C-19 Terpenolides from Thapsia garganica and their possible biogenesis. Journal of Natural Products (2005) 68, 1213-7.
Morgan AJ, Churchill GC, Masgrau R, Ruas M, Davis LC, Billington RA, Patel S, Yamasaki M, Thomas JM, Genazzani AA, Galione A. Methods in cyclic ADP-ribose and NAADP research. In Calcium Signalling, Ed J. W. Putney. (2005)
Billington RA, Tron GC, Reichenbach S, Sorba G, Genazzani AA. Role of the nicotinic acid group in NAADP receptor selectivity Cell Calcium. 2005, 37(1); 81-86.
Morgan AJ, Churchill GC, Masgrau R, Ruas M, Davis LC, Billington RA, Patel S, Yamasaki M, Thomas JM, Genazzani AA, Galione A. Methods in cyclic ADP-ribose and NAADP research. In Calcium Signalling, Ed J. W. Putney. (2005)
Billington RA, Tron GC, Reichenbach S, Sorba G, Genazzani AA. Role of the nicotinic acid group in NAADP receptor selectivity Cell Calcium. 2005, 37(1); 81-86.
Billington RA, Bak J, Debbida M, Martinez-Coscolla A, Genazzani AA. Triazine dyes are agonists of the NAADP receptor Brit J of Pharmacol. 2004, 142(8):1241-6.
Billington RA, Bak J, Debbida M, Martinez-Coscolla A, Genazzani AA. Triazine dyes are agonists of the NAADP receptor Brit J of Pharmacol. 2004, 142(8):1241-6.
Billington RA, Thuring JW, Conway SJ, Packman L, Holmes AB, Genazzani AA. Production and characterization of reduced NAADP (nicotinic acid-adenine dinucleotide phosphate). Biochem J. 2004 378:275-80.
Bak J, Billington RA, Genazzani AA. Effect of luminal and extravesicular Ca2+ on NAADP binding and release properties. Biochem Biophys Res Commun. 2002 295(4):806-11.
Billington RA, Ho A, Genazzani AA. Nicotinic acid adenine dinucleotide phosphate (NAADP) is present at micromolar concentrations in sea urchin spermatozoa. J Physiol. 2002 544:107-12.
Genazzani AA, Billington RA. NAADP: an atypical Ca2+-release messenger? Trends Pharmacol Sci. 2002 23(4):165-7
Bak J, Billington RA, Timar G, Dutton AC, Genazzani AA. NAADP receptors are present and functional in the heart. Curr Biol. 2001 11(12):987-90.
Billington RA, Genazzani AA. Characterization of NAADP binding in sea urchin eggs. Biochem Biophys Res Commun. 2000 276(1):112-6.
