RESEARCH EXPERIENCE
2017 – Present Postdoctoral Fellow
MRC LMB, CAMBRIDGE
Group: Dr William Schafer
Characterising Novel Ionotropic Receptors in the Nervous System of C. elegans.
The ligand-gated ion channels (LGICs) have undergone vast gene expansion in nematodes and includes two of the main targets for anti-helminth drugs, levamisole and ivermectin. Yet the majority of C. elegans LGICs remain uncharacterised, they have no know ligand or biological function. Using Two-Electrode Voltage Clamp (TEVC) in Xenopus oocytes I have identified ligands for 13 novel channels. Interestingly some of these channels are gated by ligands that do not act as neurotransmitters in mammals including betaine, choline, and tyramine. During this project I have helped to elucidate the learning induced trafficking of a novel cationic 5-HT receptor, published in Current Biology 2021. I have also characterised a new betaine gated chloride channel and shown that betaine is neuronally produced in C. elegans and acts as a neuromodulator to control behavioural states. Finally, I also characterised a new family of choline gated chloride channels with diverse properties.
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Publications:
Iris Hardege*, J Morud*, J Yu, T Wilson, FC Schroeder, WR Schafer. Neuronally Produced Betaine Acts via a Novel Ligand Gated Ion Channel to Control Behavioural States. BioRxiv (2021) doi.org/10.1101/2021.10.29.466399
Iris Hardege*, J Morud*, WR Schafer. A novel and functionally-diverse class of nematode acetylcholine-gated ion channels. BioRxiv (2021) doi.org/10.1101/2021.10.06.463318
J Morud*, Iris Hardege*, H Liu, T Wu, MK Choi, S Basu, Y Zhang, WR Schafer. Deorphanisation of novel biogenic amine-gated ion channels identifies a new serotonin receptor for learning. Current Biology (2021) doi:10.1016/j.cub.2021.07.036 Commentary in: doi.org/10.1016/j.cub.2021.08.055
M Gadenne*, I Hardege*, D Suleski, P Jaggers, I Beets, WR Schafer, YL Chew. Neuropeptide signalling shapes feeding and reproductive behaviours in male C. elegans. BioRxiv (2021) doi.org/10.1101/2021.11.29.470485
E Kaulich, BD Ackley, YQ Tang, Iris Hardege, WR Schafer, DS Walker. Acid-sensing DEG/ENaCs control rhythmic pH changes in the C. elegans intestine. In Prep (2021)
NP. Özbey, S. Imanikia, C. Krueger, Iris Hardege, J. Morud, M. Sheng, WR. Schafer, M. Olivia Casanueva, RC. Taylor: Tyramine Acts Downstream of Neuronal XBP-1s to Coordinate Inter-tissue UPRER Activation and Behavior in C. elegans. Developmental Cell (2020); doi: 10.1016/j.devcel.2020.10.024
2013 – 2017 PhD student
UNIVERSITY OF CAMBRIDGE
Supervisor: Dr Kevin O’Shaughnessy
Investigating the Role of GIRK4 in Aldosterone Production.
Aldosterone plays a key role in salt homeostasis and blood pressure, its dysregulation accounts for up to 10% of hypertension. A significant portion of these cases are caused by aldosterone producing adenomas (APAs), which have been shown to harbour mutations in the inwardly rectifying potassium channel GIRK4. Although the role of these mutant GIRK4 channels have been well studied in vitro, little is known about the role of wild-type GIRK4 in vivo. I studied a novel patient GIRK4 mutation and assessed its functionality in vitro, applying a range of techniques including Xenopus oocyte TEVC, immunohistochemistry, confocal imaging, qPCR and cell-based assays. This work vastly enriched my technical knowledge and lead to the publication of a first author paper during the second year of my PhD. I then focused on the role of GIRK4 in vivo, utilising a previously established knockout mouse model. I took the lead on directing the project to encompass a range of techniques, which required logistical and collaborative skills in order to maintain the animal colony, and arrange services including RNAseq.
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Publications:
Iris Hardege, L Long, RA Maskari, N Figg, K M. O’Shaughnessy. Targeted disruption of the Kcnj5 gene in the female mouse lowers aldosterone levels. Clinical Science (2018); doi: 10.1042/CS20171285
Iris Hardege, S Xu, RD Gordon, AJ Thompson, N Figg, M Stowasser, R Murrell-Lagnado, K O'Shaughnessy: Novel insertion mutation in KCNJ5 channel produces constitutive aldosterone release from H295R cells. Molecular Endocrinology (2015) doi: 10.1210/me.2015-1195
RA Maskari, Iris Hardege, S Cleary, N Figg, Y Li, K Siew, A Khir, Y Yu, P Liu, I Wilkinson, K O’Shaughnessy & Yasmin. Functional characterization of common BCL11B gene desert variants suggests a lymphocyte-mediated association of BCL11B with aortic stiffness. European Journal of Human Genetics (2018). doi: 10.1038/s41431-018-0226-z
F Schumacher, K Siew, J Zhang, C Johnson, N Wood, S Cleary, RA Maskari, J Ferryman, Iris Hardege, Yasmin, N Figg, R Enchev, AKnebel, K O'Shaughnessy, T Kurz: Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia. EMBO Molecular Medicine (2015). doi: 10.15252/emmm.201505444.
2012 – 2013 Project student
BIRKBECK/UCL, ISMB
Supervisor: Dr Andrew Osborne
Characterisation of Putative Plasmodium falciparum Exported Proteins.
During malarial infection, the parasite exports a large number of proteins into the host red blood cell leading to remodelling of the host cytoskeleton, trafficking of surface antigens and evasion of the host immune response. In this project I identified four uncharacterised exported proteins and assessed their cellular localisation and binding partners by generating GFP and STREP tagged constructs expressed in cultured Plasmodium falciparum. This work laid the foundations that lead to the characterisation a novel functional domain sufficient to target a protein to the erythrocyte periphery, published in 2014.
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Publications:
S Tarr, R Moon, Iris Hardege, A Osborne: A conserved domain targets exported PHISTb family proteins to the periphery of Plasmodium infected erythrocytes. Molecular and Biochemical Parasitology (2014). doi: 10.1016/j.molbiopara.2014.07.011.
2011 – 2012 Industrial placement student
GLAXOSMITHKLINE
Industrial Placement Student
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Investigating the Effect of BET Bromodomain Inhibition on myc Family Genes
BET proteins act as epigenetic regulators by recognising acetylated lysine residues and recruiting transcription factors and chromatin remodelling complexes. These proteins present an attractive therapeutic target due to their involvement in a wide range of cancers and viral infections. I investigated the effect of various BET inhibitor molecules on RNA and protein expression of c-myc in a panel of tumour cell lines. I gained skills in key molecular biology techniques and was able to optimise each technique to produce robust and reproducible results from the large panel of cell types and compounds studied. I also became proficient in planning experiments, data analysis, presentation and producing detailed reports to GSK’s intellectual property guidelines. Strong emphasis on teamwork within the industry also aided my development of a strong work ethic and good inter-personal working relationships.
2009 – 2010 Summer student
HULL UNIVERSITY
Supervisor: Dr. Jörg Hardege
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Studying the Influence of Ocean Acidification on Marine Polychaetes and Determination of Sex Pheromones in Shore Crabs, Carcinus maenas.
Coastal field work collection and maintenance of animals. Extracting urine samples from male Carcinus maenas. Behavioural and fertility experiments using sex pheromones in Nereis polychaetes.