Neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease are associated with the accumulation of misfolded proteins, resulting in cellular dysfunction and cell death. The current treatments are primarily aimed at providing symptom relief, rather than targeting underlying mechanisms leading to protein misfolding. Studies in a range of model organisms, including C. elegans, have shown that enhancing proteostasis capacity via a moderate elevated expression of cyto-protective chaperones, has tremendous potential for therapeutic applications. This is achieved by a conserved regulatory mechanism mediated by the master regulator of cellular stress responses, HSF1. Because of the major role Hsp90 plays in the regulation of HSF1 activity via direct interaction, Hsp90 inhibition promotes HSF1 activity and leads to increased expression of chaperones.
Adhirons are novel non-antibody scaffold proteins that allow for the targeted inhibition of protein-protein interaction. The major objective of this study is to develop Adhiron technology as a chemical-genetic approach in an intact organism to selectively inhibit the Hsp90-HSF1 interaction and induce HSF1 transcriptional activity to enhance cell-specific and organismal proteostasis. This enhanced proteostasis through Adhiron-mediated inhibition of Hsp90 can be directly tested by employing a range of C.elegans models for protein misfolding diseases, such as Alzheimer’s disease.
Developing the in-vivo utility of Adhirons in an intact metazoan for the first time will allow for the specific manipulation of biological processes more effectively than RNAi, thus adding to the C. elegans genetics toolkit.
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International or domestic self-funded or scholarship/fellowship PhD students are always welcome to apply. We are looking for highly motivated candidates with a passion and curiosity to understand the mechanisms of protein quality control that allow to find treatments for aging and neurodegenerative diseases. Ideally you have a solid background in biochemistry, genetics, molecular biology and/or cell biology. International students must have a good command of both written and spoken English.
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van Oosten-Hawle, P., Porter, R.S., Morimoto, R.I., Cell (2013); 153(6): 1366-78.
Adhiron: a stable and versatile peptide display scaffold for molecular recognition applications. Christian Tiede, Anna Tang, Sarah Deacon, Upasana Mandal, Joanne Nettleship, David Harrison, Robin Owen, Ray Owens, Suja George, Darren Tomlinson, Michael McPherson. Protein Eng Des Sel. 27(5):145-55. 2014; doi: 10.1093/protein/gzu007.