Dr. Maria Fragiadaki, BSc, MPhil, PhD
Intermediate Kidney Research UK Fellow
& Thomas-Berry and Simpson Fellow
Department of Infection, Immunity & Cardiovascular Disease
University of Sheffield
Beech Hill Road
Tel: +44 (0) 114 215 9527
Fax: +44 (0) 114 271 1863
I am an Intermediate non-clinical Research Fellow, funded by Kidney Research UK (2015 - ). I additionally hold the named ‘Thomas-Berry and Simpson’ Fellowship within the University of Sheffield. My long-term goal is to better understand the molecular and cellular events leading to the development of renovascular disease in patients with polycystic kidney disease.
My PhD was obtained from Imperial College London (2005-2008), under the mentorship of Prof George Bou-Gharios and Prof Patrick Maxwell. During my PhD I studied the transcriptional control of the collagen 1 alpha 2 gene in renal fibrosis using transgenic mice. I then took my first post-doc position in the laboratory of Prof Roger M Mason at Imperial College London aiming to better understand connective tissue growth factor signalling in diabetic nephropathy, using murine models of disease (2008-2011). My senior post-doctoral position was in the laboratory of Dr Matrin Zeidler, scientific director of the Wellcome-Trust Funded Sheffield siRNA screening facility, at the MRC center for Developmental and Biomedical Genetics Centre (2011-2013). With the guidance of Dr Zeidler, I used siRNA-based functional screening to study JAK-STAT regulating genes of unknown molecular function. During this position, I became interested in a molecule called ANKHD1 which we identified as a strong regulator of the JAK/STAT pathway via regulating the levels of JAK/STAT receptors.
My group studies the interplay between JAK-STAT signalling molecules and the development of disease. We combine genetic, molecular, biophysical and bioinformatics approaches to address key questions by utilizing mouse genetic models of disease. Our recent work is focused on the immune-modulating JAK/STAT signalling pathway and its critical role in reno-vascular dysfunction. My long-term goal is to learn more about the molecular and cellular mechanisms that govern pathogenesis and to develop new therapeutic targets for kidney patients.
My 4 areas of focus are:
1) Which signalling pathways are critical in the development of Autosomal Dominant Polycystic Kidney Disease?
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a monogenic, multi-organ disease affecting both the kidneys and the vasculature, currently remaining without a cure. The molecular mechanisms leading to pathogenesis are poorly understood.
To address this, I have received funding from the Academy of Medical Sciences (Springboard Fellowship Award - 2018-2020) to combine RNAseq transcriptomics and functional siRNA screening technologies to identify and characterize key genes involved in cystogenesis (the generation of cysts).
2) How does Ankyrin Repeat and Single KH Domain 1 (ANKHD1) enhance cystic disease?
Ankyrin Repeat and Single KH Domain 1 (ANKHD1) is a protein first discovered in Drosophila as a regulator of photoreceptor development (https://www.ncbi.nlm.nih.gov/pubmed/11782402). Recently I uncovered that ANKHD1 controls cell proliferation by directly binding to and modulating a subset of tumour-suppressor microRNAs (https://www.ncbi.nlm.nih.gov/pubmed/29695508). microRNAs are involved in the pathology of polycystic kidney disease, which is also a condition characterized by increased proliferation and elevated JAK/STAT signalling. We have established models to study cyst progression both in vitro (Figure 1) and in vivo (Figure 2). I am currently investigating the molecular mechanism employed by ANKHD1 to control proliferation in ADPKD via JAK/STAT regulation. This work is funded by Kidney Research UK via my Intermediate Fellowship (2015-2019).
3) Can Growth-hormone antagonism prove beneficial in treating ADPKD?
I have recently made the novel observation that growth hormone is enhanced by 10-fold in mice with polycystic kidneys (https://www.ncbi.nlm.nih.gov/pubmed/28104302). Growth hormone (GH) can activate JAK/STAT signalling via engaging with growth hormone receptors, which are present in the kidney (figure 3). To study proof-of-principle whether GH is contributing to disease, I have received funding in the form of a PhD studentship (2017-2020; held by Ms Fiona MacLeod) to examine whether a novel GH antagonist can reduce cyst formation in mouse and human models of ADPKD.
4) Is JAK2/STAT5 involved in the development of endothelial dysfunction?
A common symptom of ADPKD is the development of endothelial dysfunction and associated intracranial aneurysms. We have strong evidence that STAT5 is expressed in vascular endothelial cells where it regulates inflammation (figure 4). To explore the role of STAT5 in vascular inflammation further I initiated a collaboration with Prof Paul C Evans, together we received a British Heart Foundation project grant (2017-2020). Dr Hannah Roddie is currently performing RNA-seq to identify the repertoire of genes affected by STAT5 in the vasculature and perform studies in genetic mouse models of endothelial dysfunction.
2018 Academy of Medical Sciences Springboard
2017 Women Academic Returner’s Programme (WARP)
2016 Intermediate Kidney Research UK Fellowship
2014 Women Academic Returner’s Programme (WARP)
2013 Thomas Berry and Simpson Fellowship
2011 Young Life Scientist Prize, Biochemical Society
2010 Lockwood Award, Renal Association
2008 Young Renal Scientist of the year, Renal Association
2008 Walls Travel Bursary, Renal Association
2007 Best PhD Poster Prize, Imperial College London
2005 Kidney Research UK PhD Studentship, Imperial College
- Growth-Hormone/STAT5 signalling in the polycystic kidney – using single cell RNA-Seq to unravel pathogenesis - Academy of Medical Sciences Springboard Fellowship, £93,245; PI: M Fragiadaki.
- Can inhibition of GH protect the kidney from development of polycystic kidney disease? – University of Sheffield; Departmental PhD Studentship, £90,000; PI: M Fragiadaki co-I: J Sayers.
- STAT5 signalling in atherosclerosis – British Heart Foundation; Project grant, £225,000; PI: Paul C Evans co-I: M Fragiadaki.
- Identification of the role of ANKHD1 as a novel regulator of the JAK-STAT pathway in autosomal dominant polycystic kidney disease – Kidney Research UK; Intermediate Fellowship, £141,204; PI: M Fragiadaki.
- Is STAT5 involved in polycystic kidney disease? – University of Sheffield; Thomas-Berry and Simpson Fellowship, £210,000; PI: M Fragiadaki.
- Member of the Renal Scientists Working Party, 2018 – present.
- Senior Editor of Journal of Inflammation.
- Academic Editor of PLOS ONE.
- Scientific editor of International Journal of Experimental Pathology.
- Grant reviewer for Medical Research Council, Kidney Research UK, Diabetes UK and Rosetrees Trust.
- Manuscript reviewer for Plos One, Scientific reports, Kidney International, Int J Exp Pathology, Diabetes and Matrix Biology.
- Member of the Renal Scientist Working Party (Renal Association’s scientists group).
- Biochemical Society.
- Renal Association.
- British Society for Cell Biology.
- British Society for Cardiovascular Disease.
For key publications see below. For a full list of publications click here.
- Patera F, Cudzich-Madry A, Huang Z & Fragiadaki M (2019) Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis. Scientific Reports, 9. View this article in WRRO
- Fisher KH, Fragiadaki M, Pugazhendhi D, Bausek N, Arredondo MA, Thomas SJ, Brown S & Zeidler MP (2018) A genome-wide RNAi screen identifies MASK as a positive regulator of cytokine receptor stability.. Journal of Cell Science, 131(13). View this article in WRRO
- Fragiadaki M & Zeidler MP (2018) Ankyrin repeat and Single KH domain 1 (ANKHD1) drives renal cancer cell proliferation via binding to and altering a subset of miRNAs.. The Journal of Biological Chemistry, 293, 9570-9579. View this article in WRRO
- Feng S, Bowden N, Fragiadaki M, Souilhol C, Hsiao S, Mahmoud M, Allen S, Pirri D, Ayllon BT, Akhtar S , Thompson AAR et al (2017) Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites.. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(11), 2087-2101. View this article in WRRO
- Fragiadaki M, Lannoy M, Themanns M, Maurer B, Leonhard WN, Peters DJM, Moriggl R & Ong ACM (2017) STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease. Kidney International, 91(3), 575-586. View this article in WRRO
- Luong LA, Fragiadaki M, Smith J, Boyle J, Lutz J, Dean JLE, Harten S, Ashcroft M, Walmsley SR, Haskard DO , Maxwell PH et al (2013) Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination.. Circ Res, 112(12), 1583-1591.
- Fragiadaki M, Hill N, Hewitt R, Bou-Gharios G, Cook T, Tam FW, Domin J & Mason RM (2012) Hyperglycemia causes renal cell damage via CCN2-induced activation of the TrkA receptor: implications for diabetic nephropathy.. Diabetes, 61(9), 2280-2288.
- Fragiadaki M, Witherden AS, Kaneko T, Sonnylal S, Pusey CD, Bou-Gharios G & Mason RM (2011) Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo. Matrix Biology, 30(7-8), 396-403.
- Fragiadaki M & Mason RM (2011) Epithelial-mesenchymal transition in renal fibrosis - evidence for and against. International Journal of Experimental Pathology, 92(3), 143-150.
- Fragiadaki M, Ikeda T, Witherden A, Mason RM, Abraham D & Bou-Gharios G (2011) High doses of TGF-β potently suppress type I collagen via the transcription factor CUX1. Molecular Biology of the Cell, 22(11), 1836-1844.