Dr Anna Moles Fernandez
- Email: email@example.com
My translational research focuses on identifying new therapeutic targets for liver and kidney disease treatment. This is key in order to design better and more specific drugs. I am particularly interested in the cellular and molecular pathways driving disease progression, with an emphasis on protease biology. Proteases are currently in the spotlight for anti-cancer drug development. Despite being classically considered to be only protein-degrading enzymes, over the last decades this paradigm has changed with increasing numbers of physiological (antigen processing, apoptosis, etc.) and pathological (cancer, atherosclerosis, etc.) roles attributed to proteases.
Our most recent research shows an important role for lysosome protease, CtsD, in acute and chronic kidney disease progression.
Kidney disease represents the 12th cause of death in the world. It affects 8-16% of the population worldwide and in the UK it is estimated that there are 3.5 million people with kidney disease. Due to limited specific treatments, more than two million patients require dialysis or transplant worldwide every year. Therefore better and more specific treatments are urgently needed.
Our research has shown that CtsD inhibition slowed kidney disease progression, opening new avenues for the use of lysosomal protease inhibitors as possible treatments for kidney disease.
My translational research focuses on identifying new therapeutic targets to design new and better drugs for liver and kidney disease treatment. I am particularly interested in the cellular and molecular pathways driving disease progression, with an emphasis on protease biology.
During my PhD in JC Fernandez-Checa's lab, IDIBAPS, IIBB-CSIC, Barcelona, Spain we discovered a new therapeutic axis, acidic sphingomyelinase-cathepsin B/D in liver fibrosis (Hepatology, 2009; Am J Pathol, 2010). In addition, we described CtsB as a potential target for the treatment of liver fibrosis in patients with Niemann-Pick disease (NPD), which is a rare lysosomal storage disorder caused by recessive mutations on the acidic sphingomylinase gene (J Biol Chem, 2012). After finishing my PhD I moved to Newcastle Upon Tyne, UK, to work with Prof Mann and Dr Oakley in the study of post-translational modifications of NFκ-B. During my postdoc I led three independent projects. Our first work demonstrated the use of competing NFκ-B peptides as beneficial therapy to reduce liver fibrosis without affecting the innate immune response (Hepatology, 2012). Our second paper unravelled a new TLR2/S100A9/CXCL-2 signalling network which is essential for neutrophil recruitment in liver disease (J Hepatol, 2014). Our last paper, in collaboration with Prof Perkins, ICaMB, described a novel regulatory mechanism for NFκ-B in vivo and dissected its implications in liver cancer (Oncogene, 2016).
Over my career I have trained in top international and multidisciplinary teams. Learning from the best in the field has given me the knowledge, confidence and drive to develop my independent research. I am currently studying the role of proteases in kidney disease trying to identify relevant novel pathways for disease progression. Increasing our understanding around kidney disease biology is crucial in order to find new and better drugs. Better treatment options are urgently needed because:
1. Kidney disease is the 12th cause of death in the world.
2. According to the WHO kidney disease is the 17th cause for loss of quality “healthy” years of life.
3. It affects 8-16% of the population worldwide and in the UK it is estimated that there are 3.5 million people with kidney disease.
4. Due to limited specific treatments, more than two million patients require dialysis or transplant worldwide yearly
5. Acute and chronic kidney disease treatment represents combined 2.5% of the annual NHS budget at around £2 billion.
My research is funded by Newcastle University, NIHR Newcastle Biomedical Research Centre, Wellcome Trust Institutional Strategic Support and Northern Counties Kidney Research Fund (NCKRF).
If you are interested about our past or current research please get in touch.
Ongoing, MRes supervision: Autophagy, implications for chronic kidney disease.
Ongoing, PhD supervision: Role of lysosomal cathepsins in chronic kidney disease
2016, PhD supervision: Lysosomal protease cathepsin D, new driver of apoptosis during acute kidney injury
2013, BSC student supervision: Identifying the signalling events controlling phosphorylation of the RelA.
2012, BSC student supervision: Determining the anti-fibrotic potential of a novel cell targeted peptide competitor of RelA serine 536 phosphorylation in liver injury.
Supervision on a daily basis of technical staff within the team.
- Fearn A, Situmorang GR, Fox C, Oakley F, Howarth R, Wilson CL, Kiosia A, Robson MG, Mann DA, Moles A, Sheerin NS. The NF-kB1 is a key regulator of acute but not chronic renal injury. Cell Death and Disease 2017, 8, e2883.
- Moles A, Butterworth JA, Sanchez A, Hunter JE, Leslie J, Sellier H, Tiniakos D, Cockell SJ, Mann DA, Oakley F, Perkins ND. A RelA(p65) Thr505 phospho-site mutation reveals an important mechanism regulating NF-kB dependent liver regeneration and cancer. Oncogene 2016, 35(35), 4623–4632.
- Fox C, Cocchiaro P, Oakley F, Howarth R, Callaghan K, Leslie J, Luli S, Wood KM, Genovese F, Sheerin NS, Moles A. Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease. Scientific Reports 2016, 6, 20101.
- Cocchiaro P, Fox C, Tregidgo NW, Howarth R, Wood KM, Situmorang GR, Pavone LM, Sheerin NS, Moles A. Lysosomal protease cathepsin D; a new driver of apoptosis during acute kidney injury. Scientific Reports 2016, 6, 27112.
- Fox C, Howarth R, Callaghan K, Wood KM, Oakley F, Sheerin N, Moles A. Pepstatin A improves renal fibrosis by impairing UPA lysosomal recycling. In: 52nd ERA-EDTA Congress. 2015, London, UK: Oxford University Press.
- Moles A, Butterworth J, Hunter JE, Sanchez AM, Tiniakos D, Mann D, Oakley F, Perkins ND. Thr505 RelA phosphorylation controls liver proliferative response and supresses NF-kappa B tumor-promoting activities. In: 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2015. 2015, San Francisco, California: John Wiley & Sons, Inc.
- Moles A, Murphy L, Wilson CL, Bagchi Chakraborty J, Fox C, Park EJ, Mann J, Oakley F, Howarth R, Brain J, Masson S, Karin M, Seki E, Mann DA. A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. Journal of Hepatology 2014, 60(4), 782-791.
- Moles A, Sanchez AM, Banks PS, Murphy LB, Luli S, Borthwick L, Fisher A, O'Reilly S, van Laar JM, White SA, Perkins ND, Burt AD, Mann DA, Oakley F. Inhibition of RelA-Ser536 phosphorylation by a competing peptide reduces mouse liver fibrosis without blocking the innate immune response. Hepatology 2013, 57(2), 817-828.
- Fullard N, Moles A, OReilly S, vanLaar JM, Faini D, Diboll J, Reynolds NJ, Mann DA, Reichelt J, Oakley F. The c-Rel subunit of NF-κB regulates epidermal homeostasis and promotes skin fibrosis in mice. 2013.
- Moles A, Tarrats N, Fernández-Checa JC, Marí M. Cathepsin B Overexpression Due To Acid Sphingomyelinase Ablation Promotes Liver Fibrosis in Niemann Pick Disease. Journal of Biological Chemistry 2012.
- Pritchett J, Harvey E, Athwal V, Berry A, Rowe C, Oakley F, Moles A, Mann DA, Bobola N, Sharrocks AD, Thomson BJ, Zaitoun AM, Irving WL, Guha IN, Hanley NA, Hanley KP. Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans. Hepatology 2012, 56(3), 1108-1116.
- Moles A, Oakley F, Mann DA. A peptide mimetic of the functional SER536 phosphorylation site in NF-kappa B (RELA) inhibits liver fibrosis. In: Journal of Hepatology: 46th Annual Meeting of the European Association for the Study of the Liver (EASL). 2011, Berlin, Germany: Elsevier BV.
- Tarrats N, Moles A, Morales A, Garcia-Ruiz C, Fernández-Checa J, Mari M. Critical role of TNF-receptor 1 but not 2 in hepatic stellate cell proliferation, extracellular matrix remodeling and liver fibrogenesis. Hepatology 2011.
- Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, Ellis E, Lakey AF, Burt AD, Douglass A, Wright MC, White SA, Jaffre F, Maroteaux L, Mann DA. Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease. Nature Medicine 2011, 17(12), 1668-U189.
- Moles A, Tarrats N, Morales A, Dominguez M, Bataller R, Caballeria J, Garcia-Ruiz C, Fernández-Checa JC, Mari M. Acidic sphingomyelinase controls hepatic stellate cell activation and in vivo liver fibrogenesis. American Journal of Pathology 2010.
- Moles A, Tarrats N, Fernández-Checa JC, Marí M. Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology 2009.
- Marí M, Colell A, Morales A, Caballero F, Moles A, Fernández A, Terrones O, Basañez G, Antonsson B, García-Ruiz C, Fernández-Checa JC. Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 2008.
- Cònsol G, Moles A, Ricart-Jané D, Llobera M. An in situ perfusion protocol of rat epididymal adipose tissue useful in metabolic studies. Journal of Lipid Research 2005.