About the Project
Signaling systems allow the cell to perceive its environment to control and coordinate cellular activities accordingly. They are crucial for chemosensory detection, efficient homeostasis, proper development, immunity, and for cognitive processes in higher organisms. Errors in cellular signal perception and processing cause severe human pathologies including cancer, diabetes, and immune disorders.
The discovery of taste and smell related signaling systems in non-chemosensory tissues such as the gut, lung, and pancreas present new therapeutic options for disease treatments, and reinforce the traditional link between nutrition and health. In fact cellular signaling systems are the target for the majority of clinically used medicines and are also of crucial importance for the nutrition, flavor and fragrance industries. However, development times for new intervention strategies that focus on cellular signaling are excessively long, with associated high costs. In addition, the lack of effective screening platforms for a number of high value applications involving signaling has severely adverse effects on innovation and discovery.
The Berger group in Bristol is part of SynSignal, a European Commission project that addresses these issues by providing new and sophisticated synthetic biology tools to overcome the challenges facing signaling-based development and innovation (www.synsignal.eu). Funded by SynSignal, a PhD project is available immediately that combines state-of-the-art genome engineering, with cutting-edge biochemistry and imaging technology to create GPCR/G-proteins/Arrestin-based synthetic signaling pathways for next-generation drug discovery. The project builds on advanced baculovirus-based multigene delivery tools we have developed [1-5], for highly efficient transduction of a wide range of cell-types including primary cells.
You will optimize these tools employing recent recombineering and editing techniques (CRISRP/Cas9) and implemented BRET-based assays with our industrial partner in SynSignal, Geneva Biotech (www.geneva-biotech.com), including secondments. A collaboration with the Weyand lab, University of Cambridge (http://www.bioc.cam.ac.uk/people/uto/weyand), a leader in GPCR structural biology, is in place for biochemical and structural studies of signaling cascades created.
Bristol is a Centre for Synthetic Biology in UK (BrisSynBio, www.bristol.ac.uk/brissynbio/) and excellent equipment and know-how is available in newly refurbished laboratories. We are looking to fill this PhD post as soon as possible.
In a dynamic and interdisciplinary team, integrated in BrisSynBio and tightly interacting with our academic and industrial partners in SynSignal, you will:
• Implement a development program consisting of i) Design & Engineering, ii) DNA Assembly and Protein Production, and iii) Testing to accumulate a toolbox of synthetic parts, cell lines, and complete signaling circuits.
• Develop tools for this signaling toolbox with broad combinatorial potential applicable for different types of signaling cascades.
• Develop whole synthetic signaling pathways based on GPCRs, G-proteins and Arrestins, which are applicable as screening platforms for new medicines, particularly Cancer and Diabetes.
• Characterize these synthetic signaling pathways with state-of-the-art imaging and BRET-based assays including small molecule ligand screening.
Keywords: Synthetic Biology, Cellular Signaling, Genome Engineering, MultiBac, GPCR, Imaging, Biochemistry, Biotechnology, Molecular Biology
References
1. Berger et al, Nature Biotechnology 2004 22(12):1583-7.
2. Fitzgerald et al, Nature Methods 2006 3(12):1021-32.
3. Bieniossek et al, Nature Methods 2009 Jun;6(6):447-50.
4. Reich et al. Nature 2014 Dec 18;516(7531):361-6.
5. Berger & Poterszman. Bioengineered 2015 [Epub ahead of print] PMID:26488462
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