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Discovery of peptide ligands of endoplasmic reticulum (ER) chaperone ERp44 that counter metabolic syndrome

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  • Full or part time
    Prof A Mitra
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

We are seeking a well-qualified and highly motivated candidate for the position of a doctoral student to carry out a peptide-based drug-design project involving a multi-disciplinary approach. The project targets the interaction between endoplasmic reticulum (ER) chaperone ERp44 and the collagenous hormone adiponectin. Adiponectin, abundantly and exclusively secreted from adipocytes (fat cells), exerts a wide range of beneficial functions against obesity-associated pathologies such as type2 diabetes and is a potent biotherapeutic. Under obesity-induced ER stress, dysregulation of ERp44 partly leads to sequestration of adiponectin in ER. We are exploring the action of rationally designed peptides that may interfere in ERp44-adiponectin interaction to release the aberrantly trapped adiponectin as a means of mitigating the onset of metabolic syndrome in obesity.

The interdisciplinary project in collaboration with Dr. Yu Wang at University of Hong Kong combines rationally designed peptide synthesis, biophysical characterization of the binding of these peptides with ERp44, and examination of their action in cellulo and in vivo towards elevating the level of circulating adiponectin. A 3-year funding from the Health Research Council of New Zealand supports this project. The candidate should have a background in one or more of the following disciplines: Structural Biology, biophysics, protein biochemistry, peptide synthesis.

The peptide synthesis will be carried out in an in-house state-of-the-art facility. The biophysical instrumentation suite includes ITC, DSC, DLS, SEC-MALLS, UV-Vis, fluoresecence spectrophotometer, Mass Spectrometry, NMR and CD. We have a modern in-house X-ray suite and a crystallization robot. We also have frequent access to the Australian Synchrotron facility.

For further information, please send a current CV and contact to Dr. Alok K. Mitra, School of Biological Sciences, University of Auckland, Auckland, New Zealand. Tel: +64 09 923 8162, E-mail: [Email Address Removed]

References

1. Radjainia, M, Wang, Y and Mitra, AK. Structural polymorphism of oligomeric adiponectin visualized by electron microscopy. J Mol Biol, 2008. 381(2): 419-30.
2. Radjainia, M, Huang, B, Bai, B, Schmitz, M, Yang, SH, Harris, PW, Griffin, MD, Brimble, M A, Wang, Y and Mitra, AK. A highly conserved tryptophan in the N-terminal variable domain regulates disulfide bond formation and oligomeric assembly of adiponectin. FEBS J, 2012. 279(14):2495-507.
3. Harris PW, Hampe L, Radjainia M, Brimble MA, Mitra AK. An investigation of the role of the adiponectin variable domain on the stability of the collagen-like domain. Biopolymers. 2014 Jul;102(4):313-214.
4. Hampe, H, Radjainia, M, Xu, C, Harris, PWR, Bashiri, G, Goldstone, DC, Brimble, MA, Wang, Y, Mitra, AK. Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44. Journal of Biological Chemistry 2015. 290: 18111-1812.
5. Hampe L, Xu C, Harris PWR, Chen J, Liu M, Middleditch M, Radjainia M, Wang Y, Mitra AK. Synthetic peptides designed to modulate adiponectin assembly improve obesity-related metabolic disorders. Br J Pharmacol. 2017 Sep 25. doi: 10.1111/bph.14050.



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