Dr Maria Fragiadaki

Profile

Dr Maria Fragiadaki was appointed Senior Lecturer at Queen Mary University of London (QMUL) in 2022. Her lab is based at the William Harvey Research Institute, Charterhouse Square. She is awarded a UKRI ‘Future Leaders Fellowship’ (2021-2027). She previously held a Kidney Research UK Intermediate Fellowship and a Springboard Award from the Academy of Medical Sciences. 

She received a PhD in Molecular Medicine from Imperial College London, Hammersmith Campus (2009), a BSc (with honours) in Genetics from the University of Aberdeen (2005) and held post-doctoral positions at Imperial and the University of Sheffield MRC Centre for Biomedical Genetics. 

Her laboratory is interested in the elucidation of the pathways that enhance the healthy lifespan, with a particular focus on proliferation, inflammation and cellular stress in the context of kidney and cardiovascular disease. Specifically, we aim to elucidate the intricate interplay between RNA and RNA binding proteins in determining cellular homeostasis in renal epithelial and vascular cells in vitro and in vivo using models of disease.   

Research

Group members
Current: Dr Fiona Macleod (PDRA); Dr Maria-Eirini Terzenidou (PDRA); Dr Ebtehal (PDRA); Ms Jordan Mullenger (PhD student)
Past: Dr Areej Alahmadi; Ms Foteini Patera

Summary 

Fragiadaki group: Investigating the roles of RNA-binding proteins in health and disease. The group has 4 main areas of interest, which are summarised below:

1. Investigating the role of RNA-binding proteins (e.g. ANKHD1) in the context of Renal and Cardiovascular Disease
A major focus of the Fragiadaki group is to investigate the effect and specific contribution of RNA-binding proteins and their interactors (nucleic acids or other proteins) to health and disease. RNA-binding protein (RBPs) traditionally belong to the ‘undruggable’ genome and hence we know little about their activities. However, recent advancements in siRNA-based therapeutics have made RBPs new drug targets. Specifically in the development and progression of renal and cardiovascular complications. We hypothesise that by elucidating the molecular mechanisms governing key RNA pathways we will gain insights into the underlying pathophysiology, with the ultimate aim to develop targeted therapies and improve patient outcomes. 

Methodologies:
We use a combination of next-generation sequencing, RIP-seq, mass-spectrometry and biochemistry to uncover the pathways that modulate disease progression. This work is funded by UKRI. 

2. Study cytokine signalling (e.g. JAK/STAT) in Polycystic Kidney Disease (PKD)
PKD is the most common genetic cause of renal failure, affecting millions of people worldwide but currently lacking a cure. The Fragiadaki group has pioneered the work that revealed the involvement of JAK2 (Patera et al, 2019) and Growth Hormone/STAT5 (Fragiadaki et al, 2017) in the progression of PKD. We have showed that abnormally high activation of JAK2, due to elevated growth hormone levels, leads to increased proliferation, which is detrimental for the progression of PKD. Ongoing efforts in the lab, using cellular models and model organisms have showed that inhibition along this pathway is of therapeutic benefit (Patera F et al, 2019). 

Methodology:
We use spatial transcriptomics to gain spatial insight of the transcriptional changes that take play in the polycystic kidney. We combined this with antibody-based histology, molecular biology and high-resolution microscopy to unravel the novel effects of Growth Hormone/JAK/STAT pathway activity and its inhibition in PKD. 

3.  Drivers of Inflammation in the kidney and vascular network in PKD
PKD presents with kidney abnormalities but also with defects in other organ systems. In addition to the kidney, the vascular network is also damaged in patients with PKD, who often present with intracranial aneurysm. One unifying reason that explains the kidney and vascular damage is the underlying inflammation and fibrosis, which is mediated by several pathways, currently under investigation in the Fragiadaki lab. An analysis of multiple microRNA sequencing and microarray profiles revealed that inflammation (in addition to proliferation, see project number 1) are key drivers of disease progression (Fragiadaki, 2022 PMID: 35150832). Yet inflammation is one of the least studied areas in PKD. Our group aims to use unbiased methodology together with biochemistry to elucidate the inflammatory pathways that govern ADPKD development. 

4. New drivers of atherosclerosis – focusing on the RNA binding protein ANKHD1
Atherosclerosis or excessive deposition of lipids in arteries results in cardiovascular disease (CVD), a number one cause of deaths worldwide. Our group is taking a new approach by studying the contribution of RNA binding protein in models of atherosclerosis. 

Methodologies: 
We use Human Umbilical Vain Endothelial (HUVEC) or Human Coronary Arterial Endothelial (HCAEC) cells to study how certain genes affect the physiology of endothelial cells with a special focus on inflammation, proliferation and senescence.  

Key Publications

1. Mullenger, J.L., Zeidler, M.P., Fragiadaki, M. Evaluating the Molecular Properties and Function of ANKHD1, and Its Role in Cancer (2023) International Journal of Molecular Sciences, 24 (16), art. no. 12834
2. Souilhol, C., Ayllon, B.T., Li, X., Diagbouga, M.R., Zhou, Z., Canham, L., Roddie, H., Pirri, D., Chambers, E.V., Dunning, M.J., Ariaans, M., Li, J., Fang, Y., Jørgensen, H.F., Simons, M., Krams, R., Waltenberger, J., Fragiadaki, M., Ridger, V., De Val, S., Francis, S.E., Chico, T.J.A., Serbanovic-Canic, J., Evans, P.C.JAG1-NOTCH4 mechanosensing drives atherosclerosis (2022) Science Advances, 8 (35), art. no. eabo7958
3. Fragiadaki, M. Lessons from microRNA biology: Top key cellular drivers of Autosomal Dominant Polycystic Kidney Disease (2022) Biochimica et Biophysica Acta - Molecular Basis of Disease, 1868 (5), art. no. 166358
4. Souilhol, C., Gauci, I., Feng, S., Ayllon, B.T., Mahmoud, M., Canham, L., Fragiadaki, M., Serbanovic-Canic, J., Ridger, V., Evans, P.C. Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites. (2021) Cardiovascular Research, 116 (7), pp. 1300-1310.
5. Fragiadaki, M., Macleod, F.M., Ong, A.C.M. The controversial role of fibrosis in autosomal dominant polycystic kidney disease(2020) International Journal of Molecular Sciences, 21 (23), art. no. 8936, pp. 1-15
6. Pirri, D., Fragiadaki, M., Evans, P.C. Diabetic atherosclerosis: Is there a role for the hypoxia-inducible factors? (2020) Bioscience Reports, 40 (8), art. no. BSR20200026
7. Patera, F., Cudzich-Madry, A., Huang, Z., Fragiadaki, M. Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis(2019) Scientific Reports, 9 (1), art. no. 4491 Fragiadaki, M., Zeidler, M.P. Ankyrin repeat and single KH domain 1 (ANKHD1) drives renal cancer cell proliferation via binding to and altering a subset of miRNAs (2018) Journal of Biological Chemistry, 293 (25), pp. 9570-9579
8. Fragiadaki, M., Lannoy, M., Themanns, M., Maurer, B., Leonhard, W.N., Peters, D.J.M., Moriggl, R., Ong, A.C.M. STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease(2017) Kidney International, 91 (3), pp. 575-586
9. Luong, L.A., Fragiadaki, M., Smith, J., Boyle, J., Lutz, J., Dean, J.L.E., Harten, S., Ashcroft, M., Walmsley, S.R., Haskard, D.O., Maxwell, P.H., Walczak, H., Pusey, C., Evans, P.C. Cezanne regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for Deubiquitination (2013) Circulation Research, 112 (12), pp. 1583-1591
10. Fragiadaki, M., Hill, N., Hewitt, R., Bou-Gharios, G., Cook, T., Tam, F.W., Domin, J., Mason, R.M.Hyperglycemia causes renal cell damage via CCN2-induced activation of the TrkA receptor: Implications for diabetic nephropathy (2012) Diabetes, 61 (9), pp. 2280-2288 Fragiadaki, M., Witherden, A.S., Kaneko, T., Sonnylal, S., Pusey, C.D., Bou-Gharios, G., Mason, R.M. Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo (2011) Matrix Biology, 30 (7-8), pp. 396-403

Collaborators

Internal
Prof Sian Henson; Dr Li Chan; Prof Chris Thiemermann 

Teaching

Dr Fragiadaki is committed to nurturing the next generation of researchers with a passion for teaching at all University levels from Undergraduate studies to PhD to post-PhD positions. 

Disclosures

No disclosures.