Dr Martin Zeidler
Room: D43/D43a Firth Court
Brief career history
My lab is interested in identifying and analysing regulators of the JAK/STAT pathway– a signaling cascade frequently misactivated in haematopoietic malignancies. We use both high throughput RNAi screening technologies and developmental genetic assays in Drosophila to determine the mechanisms of action of pathway regulators and their interactions in vivo.
In the news
JAK/STAT signalling in development and disease
My lab studies the regulators and roles of the JAK/STAT signal transduction cascade using a combination of human cell based approaches, Drosophila-based genetic screening and in vivo biology. This work is aimed at generating insights into human inflammatory and haematopoietic disease.
The JAK/STAT pathway transduces the signals provided by multiple cytokines, growth factors and interferons. As a consequence, it plays a central role in development, cellular proliferation, stem cell maintenance, haematopoiesis and immunity. In addition, inappropriate pathway activation is also linked to a wide range of human diseases including cancers, leukaemias, myeloproliferative neoplasms (MPNs) and inflammatory diseases such as rheumatoid arthritis. Conserved throughout evolution, the pathways biological roles have also been largely maintained and as a result, many of the findings made in low complexity model systems such as Drosophila are applicable to humans.
The Zeidler lab has collaborations with a number of high profile groups including that of Tony Green (Cambridge) and Stefan Constantinescu (Brussels). I have also collaborated and co-supervised joint PhD students with the Strutt and Smythe labs (BMS) and the Bellantuono lab (Human Metabolism). In the future, I anticipate working more closely on Drosophila haematopoiesis (with lab of Iwan Evans) and on inflammatory aspects of JAK/STAT signalling humans.
In addition, we are also developing Zebrafish models of human myeloproliferative neoplasms in collaboration with the laboratory of Dr Rob Wilkinson (Cardiovascular Science). Insights gained from this work will also inform analysis using patient material which will be undertaken with Sally Thomas and John Snowden (NHS, Haematology). Finally, ‘drug repurposing’ relating to our discovery of Methotrexate as a potent inhibitor of JAK/STAT pathway signalling will also be pursued.
Undergraduate and postgraduate taught modules
Postgraduate PhD opportunities
Developing a novel methotrexate-derived small molecule JAK/STAT pathway inhibitor
Co-supervisor: Benjamin Partridge (Chemistry)
Work in the Zeidler lab has previously identified the anti-folate drug methotrexate (MTX) as a potent JAK/STAT pathway inhibitor. Used at low doses for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, methotrexate is widely used, has a well understood toxicity profile and is a very low cost drug. Given its function as a JAK/STAT inhibitor, the potential exists to repurpose MTX for other diseases associated with inappropriate pathway activity. Such a change in clinical practice has recently been demonstrated and has significant potential to fulfill a significant unmet need.
However, while repurposing MTX has considerable potential, its long term use is also sometimes associated with potentially serious side-effects – most of which are the consequence of its inhibition of dihydrofolate reductase activity (DHFR). MTX side effects range from relatively minor gastro-intestinal discomfort and nausea to potentially serious myelosuppression and foetal loss/defects in early pregnancy. Given these undesirable characteristics, the development of novel MTX-derived compounds which retain their ability to suppress the JAK/STAT pathway, but which no longer inhibit DHFR, have the potential to define a new class of ‘next generation’ JAK/STAT pathway inhibitors.
In this project, cell based assays for JAK/STAT and DHFR activity already established in the Zeidler lab will be combined with novel medicinal chemistry approaches in the Partridge lab. The successful candidate will design and synthesize libraries of novel MTX derivatives designed to explore the chemical space around methotrexate. The candidate will then use these compounds, together with established positive and negative controls, to undertake cell based assays designed to establish the specificity, activity and toxicity of the molecules generated. Lead compounds will be refined using iterative ‘molecular evolution’ approaches and established medicinal chemistry techniques. Ultimately, compounds will be tested in pre-clinical Drosophila and mouse models of human JAK/STAT disease. In the long-term, we aim to engage with the pharmaceutical industry as a prelude to potential human clinical trials.
JAK/STAT singling and the regulation of the cytoskeleton
Co-supervisor: Dr Iwan Evans (Infection, Immunity & Cardiovascular Disease)
We have previously used the excellent developmental genetics of the Drosophila model organism to investigate the relationship between the JAK/STAT signal transduction pathway and the behaviour of fly blood cells (termed haemocytes) (Bausek & Zeidler 2013, Bina et al 2010). In addition, other researchers have shown that the JAK/STAT pathway is required to rearrange the cytoskeleton of epithelial pole cells to a mesenchymal morphology (EMT) in the developing fly ovary (Silver & Montel 2001). Simultaneously, other studies also suggest a role for human STAT3 in regulating the effectors of EMT in cancers. Taken together, all these studies suggest that the JAK/STAT pathway plays a key role in the regulation of the cytoskeletal changes involved in cell shape changes.
Using technologies developed in Evans lab, we have now have tools available with which to examine the dynamic movements of the haemocyte cytoskeleton in vivo. Using these tools, the responses of cells to stimuli such as nearby wounding or apoptotic cells can be readily examined.
In this project the successful candidate will examine the roles of JAK/STAT pathway signalling and its target genes in vivo. This work will have a particular focus on the haemocytes associated with the third instar larval imaginal discs. In particular, apoptosis of imaginal disc cells requires haemocytes to alter their morphology so as to invade these tissues to remove apoptotic corpses. We now seek to characterise the behaviour of larval haemocytes in response to apoptotic imaginal cells.
Once this ‘wild type’ behaviour has been characterised you will investigate the effect of loss- and gain-of-function mutations in the JAK/STAT pathway (and pathway target genes) on this process and how these genetic manipulations change cellular function and cytoplasmic morphology.
Ultimately this project aims to cast light on the mechanisms underpinning the cellular changes that occur in cancer metastasis.
For more information about these projects and how to apply, see our PhD opportunities page:
- Chinnaiya K, Lawson MA, Thomas S, Haider M-T, Down J, Chantry AD, Hughes D, Green A, Sayers JR, Snowden JA & Zeidler MP (2017) Low-dose methotrexate in myeloproliferative neoplasm models.. Haematologica. View this article in WRRO
- Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S & Zeidler MP (2015) Methotrexate Is a JAK/STAT Pathway Inhibitor. PLOS ONE, 10(7). View this article in WRRO
- Wells RE, Barry JD, Warrington SJ, Cuhlmann S, Evans P, Huber W, Strutt D & Zeidler MP (2013) Control of tissue morphology by Fasciclin III-mediated intercellular adhesion.. Development, 140(18), 3858-3868.
- Bausek N & Zeidler MP (2013) Gα73Β is a downstream effector of JAK/STAT signaling and a regulator of Rho1 in Drosophila hematopoiesis. J Cell Sci.
- Müller P, Kuttenkeuler D, Gesellchen V, Zeidler MP & Boutros M (2005) Identification of JAK/STAT signalling components by genome-wide RNA interference.. Nature, 436(7052), 871-875.