Dr. Maria Fragiadaki, BSc, MPhil, PhD

Intermediate Kidney Research UK Fellow
& Thomas-Berry and Simpson Fellow

Maria FragiadakiDepartment of Infection, Immunity & Cardiovascular Disease
University of Sheffield
Medical School
Beech Hill Road
Sheffield
S10 2RX
United Kingdom

Tel: +44 (0) 114 215 9527
Fax: +44 (0) 114 271 1863
Email: m.fragiadaki@sheffield.ac.uk

Biography:

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.

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.

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).

human ADPKD-derived cells

Pdk1

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.

confocal microscopy - kidney epithelial cells

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.

STAT5

Selected Awards:

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

Current Projects:

  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.
  4. 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.
  5. Is STAT5 involved in polycystic kidney disease? – University of Sheffield; Thomas-Berry and Simpson Fellowship, £210,000; PI: M Fragiadaki.

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.

Publications:

For key publications see below. For a full list of publications click here.

Journal articles