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Dr J de Navascués, Prof A R Clarke
No more applications being accepted
Funded PhD Project (Students Worldwide)
About the Project
Adult intestinal stem cells (ISCs) are the population with greatest tumour initiation potential in the gut [1,2]. Understanding how stem cells are regulated in healthy tissue can help develop new strategies for cancer treatment. ISCs maintain homeostasis by neutral competition, whereby ISCs choose stochastically whether to divide either asymmetrically into an ISC and a differentiating cell, or symmetrically into either two ISCs or two differentiating cells [3,4]. This is important for cancer initiation, as cancerous mutations could be ‘flushed out’ of the stem compartment [5], but also pre-cancerous mutations could expand through the stem cell pool [6].
Neutral competition also occurs in the Drosophila intestine [7], where we propose to address the molecular regulation underlying neutral competition. A candidate mechanism is Notch/Delta-dependent lateral inhibition, whereby stem cells would mutually inhibit their self renewal. The phenotypes of Notch signalling mutants are compatible with this view [7-11]. However, lateral inhibition requires an underlying network of of bHLH transcription factors. While there is evidence supporting the existence of such a network [11], whereby heterodimers of class A/E bHLH factors would promote the stem cell fate and be opposed by factors of the HES family (E(spl) in Drosophila) downstream of Notch, its presence and relationship with lateral inhibition has not been established in the Drosophila intestine.
We aim at identifying a class A bHLH factor involved in ISC maintenance, both by focusing on candidates known to be expressed in the intestine and by screening other known bHLH factors in Drosophila. This work will provide both mechanistic insight into ISC neutral competition and an in vivo setting where to study the roles of bHLH proteins with roles in tumourigenesis and metastasis of gastrointestinal cancers, but whose functions have not been explored in vivo.
To apply, please follow: http://www.cardiff.ac.uk/biosi/degreeprogrammes/postgraduateresearch/howtoapply/index.html
Neutral competition also occurs in the Drosophila intestine [7], where we propose to address the molecular regulation underlying neutral competition. A candidate mechanism is Notch/Delta-dependent lateral inhibition, whereby stem cells would mutually inhibit their self renewal. The phenotypes of Notch signalling mutants are compatible with this view [7-11]. However, lateral inhibition requires an underlying network of of bHLH transcription factors. While there is evidence supporting the existence of such a network [11], whereby heterodimers of class A/E bHLH factors would promote the stem cell fate and be opposed by factors of the HES family (E(spl) in Drosophila) downstream of Notch, its presence and relationship with lateral inhibition has not been established in the Drosophila intestine.
We aim at identifying a class A bHLH factor involved in ISC maintenance, both by focusing on candidates known to be expressed in the intestine and by screening other known bHLH factors in Drosophila. This work will provide both mechanistic insight into ISC neutral competition and an in vivo setting where to study the roles of bHLH proteins with roles in tumourigenesis and metastasis of gastrointestinal cancers, but whose functions have not been explored in vivo.
To apply, please follow: http://www.cardiff.ac.uk/biosi/degreeprogrammes/postgraduateresearch/howtoapply/index.html
Funding Notes
This studentship is funded by the European Cancer Stem Cell Research Institute, Cardiff University will start on the 1st October 2014. This studentship includes UK/EU tuition fees and an annual stipend. The stipend, per annum, is at least £13,863.
The studentship is open to applicants worldwide. Non-EU applicants will need to fund the difference between the UK/EU tuition fee rate and the overseas tuition fee rate.
A degree with at least 2:1 result or equivalent is required. A degree in Biology would be advantageous but any science graduate is encouraged to apply. Good understanding of Genetics would be highly desirable.
The studentship is open to applicants worldwide. Non-EU applicants will need to fund the difference between the UK/EU tuition fee rate and the overseas tuition fee rate.
A degree with at least 2:1 result or equivalent is required. A degree in Biology would be advantageous but any science graduate is encouraged to apply. Good understanding of Genetics would be highly desirable.
References
1. Barker, N. et al. 2009 Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–612. (doi:10.1038/nature07602)
2. Zhu, L. et al. 2009 nature07589. Nature 457, 603–608. (doi:10.1038/nature07589)
3. Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. 2010 Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825. (doi:10.1126/science.1196236)
4. Snippert, H. J. et al. 2010 Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144. (doi:10.1016/j.cell.2010.09.016)
5. Vermeulen, L., Morrissey, E., van der Heijden, M., Nicholson, A. M., Sottoriva, A., Buczacki, S., Kemp, R., Tavaré, S. & Winton, D. J. 2013 Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998. (doi:10.1126/science.1243148)
6. Snippert, H. J., Schepers, A. G., van Es, J. H., Simons, B. D. & Clevers, H. 2013 Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO reports, n/a–n/a. (doi:10.1002/embr.201337799)
7. de Navascués, J., Perdigoto, C. N., Bian, Y., Schneider, M. H., Bardin, A. J., Martinez-Arias, A. & Simons, B. D. 2012 Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J 31, 2473–2485. (doi:10.1038/emboj.2012.106)
8. Micchelli, C. A. & Perrimon, N. 2006 Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479. (doi:10.1038/nature04371)
9. Ohlstein, B. & Spradling, A. 2006 The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474. (doi:10.1038/nature04333)
10. Ohlstein, B. & Spradling, A. 2007 Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315, 988–992. (doi:10.1126/science.1136606)
11.Bardin, A. J., Perdigoto, C. N., Southall, T. D., Brand, A. H. & Schweisguth, F. 2010 Transcriptional control of stem cell maintenance in the Drosophila intestine. Development 137, 705–714. (doi:10.1242/dev.039404)
2. Zhu, L. et al. 2009 nature07589. Nature 457, 603–608. (doi:10.1038/nature07589)
3. Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. 2010 Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825. (doi:10.1126/science.1196236)
4. Snippert, H. J. et al. 2010 Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144. (doi:10.1016/j.cell.2010.09.016)
5. Vermeulen, L., Morrissey, E., van der Heijden, M., Nicholson, A. M., Sottoriva, A., Buczacki, S., Kemp, R., Tavaré, S. & Winton, D. J. 2013 Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998. (doi:10.1126/science.1243148)
6. Snippert, H. J., Schepers, A. G., van Es, J. H., Simons, B. D. & Clevers, H. 2013 Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO reports, n/a–n/a. (doi:10.1002/embr.201337799)
7. de Navascués, J., Perdigoto, C. N., Bian, Y., Schneider, M. H., Bardin, A. J., Martinez-Arias, A. & Simons, B. D. 2012 Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J 31, 2473–2485. (doi:10.1038/emboj.2012.106)
8. Micchelli, C. A. & Perrimon, N. 2006 Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479. (doi:10.1038/nature04371)
9. Ohlstein, B. & Spradling, A. 2006 The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474. (doi:10.1038/nature04333)
10. Ohlstein, B. & Spradling, A. 2007 Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science 315, 988–992. (doi:10.1126/science.1136606)
11.Bardin, A. J., Perdigoto, C. N., Southall, T. D., Brand, A. H. & Schweisguth, F. 2010 Transcriptional control of stem cell maintenance in the Drosophila intestine. Development 137, 705–714. (doi:10.1242/dev.039404)
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