Dr Maria Fragiadaki
BSc, MPhil, PhD
Department of Infection, Immunity and Cardiovascular Disease
Research Fellow
+44 114 215 9527
Full contact details
Department of Infection, Immunity and Cardiovascular Disease
The Medical School
Beech Hill Road
Sheffield
S10 2RX
- Profile
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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.
- Research interests
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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.
- 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.
- Publications
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Show: Featured publications All publications
Featured publications
Journal articles
- Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites. Cardiovascular Research. View this article in WRRO
- Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis. Scientific Reports, 9. View this article in WRRO
- 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
- 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
- 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
- STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease. Kidney International, 91(3), 575-586. View this article in WRRO
- Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination.. Circ Res, 112(12), 1583-1591.
- Hyperglycemia causes renal cell damage via CCN2-induced activation of the TrkA receptor: implications for diabetic nephropathy.. Diabetes, 61(9), 2280-2288.
- Epithelial-mesenchymal transition in renal fibrosis - evidence for and against. International Journal of Experimental Pathology, 92(3), 143-150.
- Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo. Matrix Biology, 30(7-8), 396-403.
- High doses of TGF-β potently suppress type I collagen via the transcription factor CUX1. Molecular Biology of the Cell, 22(11), 1836-1844.
All publications
Journal articles
- Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes. Nature Reviews Cardiology, 17(1), 52-63.
- Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites. Cardiovascular Research. View this article in WRRO
- β1 integrin is a sensor of blood flow direction. Journal of Cell Science. View this article in WRRO
- BS28 Endothelial STAT5A is enriched at atheroprone regions of the aorta and drives inflammation in response to low shear stress. Basic Science.
- Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis. Scientific Reports, 9. View this article in WRRO
- The Bernard and Joan Marshall Early Career Investigators and Distinguished Investigator Award 2018. Cardiovascular Drugs and Therapy. View this article in WRRO
- 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
- 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
- Response by Feng et al to Letter Regarding Article, “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites”. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(12), e199-e200.
- 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
- MP024ANKHD1 REGULATES THE JAKSTAT PATHWAY IN KIDNEY FIBROSIS. Nephrology Dialysis Transplantation, 32(suppl_3), iii437-iii437.
- STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease. Kidney International, 91(3), 575-586. View this article in WRRO
- Data on CUX1 isoforms in idiopathic pulmonary fibrosis lung and systemic sclerosis skin tissue sections. Data in Brief, 8, 1377-1380. View this article in WRRO
- Transforming growth factor-β-induced CUX1 isoforms are associated with fibrosis in systemic sclerosis lung fibroblasts. Biochemistry and Biophysics Reports, 7, 246-252. View this article in WRRO
- The application of antibotoxsome, a novel cytotoxic conjugate, in cell death in in vitro models of pancreatic, liver, breast, cervical cancer, and myeloma.. Journal of Clinical Oncology, 33(15_suppl), e12018-e12018.
- Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination.. Circ Res, 112(12), 1583-1591.
- Hyperglycemia causes renal cell damage via CCN2-induced activation of the TrkA receptor: implications for diabetic nephropathy.. Diabetes, 61(9), 2280-2288.
- Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo. Matrix Biology.
- Epithelial-mesenchymal transition in renal fibrosis - evidence for and against. International Journal of Experimental Pathology, 92(3), 143-150.
- Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo. Matrix Biology, 30(7-8), 396-403.
- High doses of TGF-β potently suppress type I collagen via the transcription factor CUX1. Molecular Biology of the Cell, 22(11), 1836-1844.
- Repression of collagen type I by TGF-beta induced CUX1. CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 28(5), S65-S65.
- In position 7 L-and D-Tic-substituted oxytocin and deamino oxytocin: NMR study and conformational insights. Amino Acids, 39(2), 539-548.
- CDP/cux is capable of strong inhibition of the COL1A2 gene. Matrix Biology, 27, 18-18.
Conference proceedings papers
- Endothelial STAT5A Is Enriched at Atheroprone Regions and Drives Inflammation in Response to Low Shear Stress. CARDIOVASCULAR DRUGS AND THERAPY, Vol. 33(2) (pp 274-274)
- The application of antibotoxsome, a novel cytotoxic conjugate, in cell death in in vitro models of pancreatic, liver, breast, cervical cancer, and myeloma.. Journal of Clinical Oncology, Vol. 33(15)
- Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites. Cardiovascular Research. View this article in WRRO
- Research group
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Group Members
- Ms Fiona MacLeod (PhD student, UoS funded)
- Ms Foteini Patera (Research Associate, WARP funded)
- Ms Daniela Pirri (PhD student, A* studentship)
- Dr. Hannah Roddie (Post-doctoral Research Associate, BHF funded)
Collaborators
- Professor Paul C Evans
- Professor Richard Moriggl
- Professor Jon Sayers
- Professional activities
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- 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.
Memberships:
- 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.
Selected awards
- 2018 Academy of Medical Sciences Springboard
- 2017 Women Academic Returner’s Programme (WARP)
- 2014 Women Academic Returner’s Programme (WARP)
- 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
- Research focus
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).
Figure 1: We use human ADPKD-derived cells which grow in three-dimensional organotypic cultures. Microscopic cysts arise which grow in size over several days. With this model we can inhibit gene expression either pharmacologically or with gene silencing strategies. We can enhance gene expression by cytokine stimulation and/or gene editing. Growth of cysts is then measured over several days and therefore inform us if a novel gene or drug may affect in vitro cystogenesis. This approach is complementary to our mouse genetic models and studies of human samples.
Figure 2: A Mouse model of polycystic kidney disease in the Fragiadaki Lab. Kidneys sections were stained with H&E. Right panel shows kidney section from mice where the Pkd1 gene was deleted in the kidney resulting in polycystic kidney disease; on the left the wild-type littermate control kidneys can be seen.
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.
Figure 3: Confocal microscopy of renal kidney sections. Top panels show normal mouse kidney epithelial cells expressing GHR (left) and STAT5 (right), while the bottom panels show GHR (left) and STAT5 (right) distribution in polycystic kidneys.
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.
Figure 4: En face staining of STAT5 followed by confocal microscopy. STAT5 was deleted in endothelial cells by crossing the endothelial-SCL-Cre-ERT into the STAT5A/B fl/fl mouse, resulting in STAT5 deletion specifically in endothelial cells following tamoxifen injections.
