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PhD Scholarships

4 Year CRUK PhD Studentship – September 2018 “Molecular Probes for Imaging Lysyl Oxidase with…

*4 Year CRUK PhD Studentship – September 2018*
_*“Molecular Probes for Imaging Lysyl Oxidase with Potential Application to the Detection of Metastasis”*_

*Drug Discovery Research Group – Professor Caroline Springer*

Tumour metastases are responsible for over 90% of cancer patient deaths, but treatment options for these late-stage patients are still very limited. Lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix such as collagens and elastin. LOX is produced and secreted into the circulation by cancer cells in response to hypoxia1,2 and is a critical mediator of tumour growth and metastatic tumour spread1-5. Expression of LOX is elevated in > 70 % of breast cancer patients with ER negative disease, in 80 % of head & neck cancer patients,6 in 33 % of primary colorectal carcinomas (CRC) and 48 % of metastatic tissues from patients with CRC,7 and in cirrhotic hepatocellular carcinoma (HCC) patients with a history of alcoholism8. Elevated LOX expression is associated with metastasis and decreased patient survival. We have shown that LOX is upregulated in PDAC and plays a fundamental role in the primary growth and metastasis of this cancer9 [Miller et al, 2015]. Furthermore, LOX appears to be required to condition the pre-metastatic niche in breast cancer by modifying the extracellular matrix, which then prepares the environment for the recruitment of bone marrow derived cells, and subsequently the cancer cells themselves1,2,4.

We have designed and discovered new LOX inhibitors for the treatment of primary and metastatic cancers and have shown effective inhibition of primary tumour growth in several tumour models and potent inhibition of lung metastases in a breast model10.

The aim of this project is to design and synthesise molecular imaging probes, with an emphasis on optical imaging, based on our potent LOX inhibitors, for the detection of LOX in biological samples and in vivo. Near infrared (NIR) fluorescence has been used for in vivo imaging due to its deeper tissue penetrance compared to usual fluorophores of lower wavelength11. The student will design NIR probes based on our LOX inhibitors or through de novo design. These probes are designed for applications in tumour detection, detection of early metastases and understanding the role of LOX in tumour growth and formation of metastases. Additionally these probes will be useful as companion biomarkers to assess the efficacy of our LOX inhibitors. This project will involve close collaboration between the Drug Discovery Unit led by Prof Caroline Springer, and the Molecular Oncology group led by Prof. Richard Marais.

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The successful candidate will learn synthetic and medicinal chemistry in the Drug Discovery Unit and will become familiar with analytical chemistry, including the use of nuclear magnetic resonance, mass spectrometry and high performance liquid chromatography. The student will gain an understanding of medicinal chemistry and drug design approaches and is expected to contribute to the design of new molecular probes The student will have the opportunity to learn biochemical and biological techniques such as enzymatic assays, cell culture and cell based assays.
1. Erler, J. T.; Bennewith, K. L.; Nicolau, M.; Dornhofer, N.; Kong, C.; Le, Q.-T.; Chi, J.-T. A.; Jeffrey, S. S.; Giaccia, A. J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006, 440, 1222-1226.
2. Erler, J. T.; Bennewith, K. L.; Cox, T. R.; Lang, G.; Bird, D.; Koong, A.; Le, Q. T.; Giaccia, A. J. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer cell 2009, 15, 35-44.
3. Gao, Y.; Xiao, Q.; Ma, H.; Li, L.; Liu, J.; Feng, Y.; Fang, Z.; Wu, J.; Han, X.; Zhang, J.; Sun, Y.; Wu, G.; Padera, R.; Chen, H.; Wong, K.-k.; Ge, G.; Ji, H. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proceedings of the National Academy of Sciences 2010, 107, 18892-18897.
4. Bondareva, A.; Downey, C. M.; Ayres, F.; Liu, W.; Boyd, S. K.; Hallgrimsson, B.; Jirik, F. R. The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells. PloS one 2009, 4, e5620.
5. Levental, K. R.; Yu, H.; Kass, L.; Lakins, J. N.; Egeblad, M.; Erler, J. T.; Fong, S. F.; Csiszar, K.; Giaccia, A.; Weninger, W.; Yamauchi, M.; Gasser, D. L.; Weaver, V. M. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009, 139, 891-906.
6. Barker, H. E.; Cox, T. R.; Erler, J. T. The rationale for targeting the LOX family in cancer. Nat Rev Cancer 2012, 12, 540-552.
7. Baker, A.-M.; Cox, T. R.; Bird, D.; Lang, G.; Murray, G. I.; Sun, X.-F.; Southall, S. M.; Wilson, J. R.; Erler, J. T. The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. J Natl Cancer Inst 2011, 103, 407-424.
8. Huang, C. S.; Ho, C. T.; Tu, S. H.; Pan, M. H.; Chuang, C. H.; Chang, H. W.; Chang, C. H.; Wu, C. H.; Ho, Y. S. Long-Term Ethanol Exposure-Induced Hepatocellular Carcinoma Cell Migration and Invasion through Lysyl Oxidase Activation Are Attenuated by Combined Treatment with Pterostilbene and Curcumin Analogues. J Agric Food Chem 2013, 61, 4326-4335.
9. Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, McGhee E, Timpson P, Leach J, McGarry L, Shanks E, Bailey P, Chang D, Oien K, Karim S, Au A, Steele C, Carter CR, McKay C, Anderson K, Evans TR, Marais R, Springer C, Biankin A, Erler JT, Sansom OJ (2015). Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 7(8): 1063-1076
10. H. Tang et al, Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface, Nature Communications, 8:14909 (2017).
11. Hong G. et al, Near-infrared fluorophores for biomedical imaging. Nature Biomed. Eng. (2017)

Informal enquiries should be addressed to Professor Caroline Springer; [email protected]

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Interested students can find full group project details, entry criteria and details on how to apply on the CRUK Manchester Institute website;
http://www.cruk.manchester.ac.uk/education/PhD-Studentships

*Closing date: Friday 19 January 2018, 2400 hrs (GMT)*
*Interview date: Wednesday 14 February 2018, Alderley Park, Cheshire*

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PhD Scholarships

PhD positions at The University of Warwick : Biological Sciences/Synthetic biology (# of pos: 4)

Our group is offering PhD positions for 2018-2019 academic year.  These studentships are hosted by The University of Warwick Doctoral Training Centres 

 Details below

1) PhD project title: Engineering microbial chemical factories to produce renewable and modified biomaterials. 

PhD is hosted via MIBT Partnership

Research Area  : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-  https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/molecularandmetabolicengineering2018/biomaterials

2) PhD project title: Development of novel halogenase enzymes for biopharmaceutical applications.

PhD is hosted via MIBT Partnership

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :- https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/molecularandmetabolicengineering2018/applications

3) PhD project title: Expanding the genetic lexicon: Developing novel tools for non-natural amino acid incorporation in to therapeutic peptides and proteins.

PhD is hosted via SynBIO DTC 

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :- https://www2.warwick.ac.uk/fac/sci/lifesci/study/pgr/studentships/synbiocdt

4) PhD project title:  Bioplastics from E. coli

PhD is hosted via SynBIO DTC

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :- https://www2.warwick.ac.uk/fac/sci/lifesci/study/pgr/studentships/synbiocdt

Applications are encouraged from UK, EU and International students.

Please be aware that International (non EU) applicants are not eligible for EPSRC/BBSRC funded studentships.

To be eligible for a full EPSRC/BBSRC award (Tuition fees and Stipend) a student must have:

  • Settled status in the UK, meaning they have no restrictions on how long then can stay and
  • Been ‘ordinarily resident’ in the UK for 3 years prior to the start of the studentship. This means they must have been normally residing in the UK (apart from temporary or occasional absences) and
  • Not been residing in the UK wholly or mainly for the purpose of full-time education. (This does not apply to UK or EU nationals).
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To be eligible for an EPSRC/BBSRC tuition fees only award:

  • Students from EU countries other than the UK are generally eligible for a fees-only award. To be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU, in the same way as UK students must be ordinarily resident in the UK.

Interested students with research experience and qualification please contact us directly. 

https://warwick.ac.uk/fac/sci/lifesci/people/bmenon/

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France Scholarships

PhD position in quantum optimal control theory at the University of Bourgogne

This PhD project aims at applying innovative mathematical tools coming

from optimal control theory to improve theoretical and experimental techniques

in Nuclear Magnetic Resonance (NMR), in Electron Spin Resonance (ESR) and in NV

centers. This approach will allow us to explore and to experimentally reach the

physical limits of the corresponding spin dynamics in presence of typical

experimental imperfections and limitations. A first objective will be to

develop new optimal control algorithms able for an inhomogeneous ensemble of

spins to maximize the signal to noise ratio per unit time of the system. A

general problem is to generalize the Ernst angle solution used in NMR, which is

only valid for a homogeneous spin ensemble. This work will be done in

collaboration with the group of S. Glaser (TUM, Munich, Germany). This approach

will find different applications in NMR and ESR where the sensitivity of the

experiment is a crucial parameter. The student will focus on a specific

experimental setup in ESR used by the group of P. Bertet (CEA, Paris Saclay),

where an important goal is the maximization of the emitted signal of spins

coupled to a microwave resonator. The student will take into account in the

numerical computation specific constraints of this experimental setup. In the

same direction, the student will also use optimal control techniques to design

new CMPG sequences accounting for the coupling between the spins and the

cavity. The same types of control techniques will also be used for manipulating

NV ensembles in collaboration with the group of T. Debuisschert (Thalès,

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Paris). This will allow the improvement of the sensitivity of the corresponding

experiments. For a more fundamental point of view, the ESR will investigate the

numerical techniques used to design robust control fields with respect to

experimental imperfections. A first objective will be to understand the

efficiency of these methods and to prove the optimality (this concept will be

to define rigorously) of the control fields. The ESR will mainly study spin

systems but it is clear that the results of this project will not be restricted

to the physical systems investigated and the techniques developed during the

PhD could be applied to other physical systems with similar properties.

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Israel Scholarships

Marie Curie Innovative Training Network (ITN) META-CAN – PhD position in Computational biology to…

The Machine Learning for Healthcare and Life Sciences group at IBM Research – Haifa is a partner in the funded Marie Curie Innovative Training Network (ITN) META-CAN. The network is a pan-European interdisciplinary and intersectoral training programme for excellence.  It brings young researchers together with world-leading academics, clinicians, and industry personnel to focus on the connections of metabolism, immune response, and cancer.

We are looking for an enthusiastic and highly-motivated early stage researcher (ESR), with a background and experience in computational biology, machine learning and/or statistics and good programming skills (preferably in Python or R). This ESR will study towards a PhD degree and, under our guidance (and in collaboration with the Technion Integrated Cancer Center), will analyze comprehensive omics data to better understand the metabolic adaptations of cancer cells to the central nervous system niche.

The right candidate will enjoy a competitive salary and outstanding work environment.

For more details see http://metacan.eu/  or contact [email protected]

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