Dr Maria Fragiadaki

BSc, MPhil, PhD

Department of Infection, Immunity and Cardiovascular Disease

Senior Research Fellow

m.fragiadaki@sheffield.ac.uk
+44 114 215 9527
+44 114 271 1863 (fax)
The Medical School

Full contact details

Dr Maria Fragiadaki
Department of Infection, Immunity and Cardiovascular Disease
The Medical School
Beech Hill Road
Sheffield
S10 2RX
Profile

For enquiries, please contact – iicd-operationalteam@sheffield.ac.uk

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

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.

  1. 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.
  2. 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.
  3. STAT5 signalling in atherosclerosis – British Heart Foundation; Project grant, £225,000; PI: Paul C Evans co-I: M Fragiadaki.
Publications

Show: Featured publications All publications

Journal articles

All publications

Journal articles

Conference proceedings papers

  • Roddie H, Fragiadaki M & Evans P (2019) 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) RIS download Bibtex download
  • Tazzyman S, Hautbergue G, Khurram A, Bryan M, Chantry A & Fragiadaki M (2015) 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) RIS download Bibtex download
Research group

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
  • 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).

Cyst progression in vitro

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.

Cyst progression in vivo

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.

Confocal microscopy of renal kidney sections.

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.

En face staining of STAT5

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. 

Links

personal website (Fragiadaki Lab)
Sheffield Kidney Research