Dissecting the role of the BBSome in ciliary effector protein trafficking
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
This project is part of an industrial collaboration between the BBSRC and GSK. The student will have the opportunity of high quality research training within both an academic and an industrial setting, and will entail a minimum of 6 months training at GlaxoSmithKline (GSK), Stevenage.
The project will investigate the so-called 'BBSome', which is a complex consisting of 8 proteins that are mutated in Bardet-Biedl syndrome (BBS). The BBSome regulates dynein-mediated retrograde intraflagellar transport along neuronal and renal primary cilia, as well as the connecting cilium of photoreceptors, and has been shown to interact with key effector proteins within each of these cell types, including DISC1, PC1 and RPGR, respectively. The aim of the research will be to use state-of-the art microscopy-based high-throughput screening to identify drugs that influence ciliary trafficking, and to investigate how mutations affecting BBSome proteins influence effector protein trafficking. The project will involve a range of techniques including cell culture, protein biochemistry, drug screening, imaging and genome editing techniques (e.g. CRISPR/Cas9), as well as work with zebrafish and mouse models of disease.
The project will investigate the so-called 'BBSome', which is a complex consisting of 8 proteins that are mutated in Bardet-Biedl syndrome (BBS). The BBSome regulates dynein-mediated retrograde intraflagellar transport along neuronal and renal primary cilia, as well as the connecting cilium of photoreceptors, and has been shown to interact with key effector proteins within each of these cell types, including DISC1, PC1 and RPGR, respectively. The aim of the research will be to use state-of-the art microscopy-based high-throughput screening to identify drugs that influence ciliary trafficking, and to investigate how mutations affecting BBSome proteins influence effector protein trafficking. The project will involve a range of techniques including cell culture, protein biochemistry, drug screening, imaging and genome editing techniques (e.g. CRISPR/Cas9), as well as work with zebrafish and mouse models of disease.
People |
ORCID iD |
| Dagan Jenkins (Primary Supervisor) | |
| Grace Freke (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/N503800/1 | 01/10/2015 | 30/09/2019 | |||
| 1635155 | Studentship | BB/N503800/1 | 30/09/2015 | 29/09/2019 | Grace Freke |
| Description | IUBMB Young Scientist Program Fellowship |
| Amount | $1,280 (USD) |
| Organisation | International Union of Biochemistry and Molecular Biology |
| Sector | Learned Society |
| Country | Canada |
| Start | 06/2018 |
| End | 06/2018 |
| Description | Structural biology and molecular genetics of IFT80 |
| Organisation | Aarhus University |
| Country | Denmark |
| Sector | Academic/University |
| PI Contribution | Together with Esben Lorentzen's group, we have a manuscript in revision at Elife journal, for which we received favourable reviews. We report of the crystal structure of IFT80. The Jenkins lab contributed as an equal senior author to this paper by creating and characterising IMCD3 cells carrying biallelic framshift mutations in Ift80, which were used to test functional hypotheses about structural domains within the protein and missense mutations found in patients with Jeune syndrome. We also visualised IFT80 within cilia for the first time using super-resolution microscopy. Lorentzena and Jenkins are joint senior and corresponding authors. |
| Collaborator Contribution | Esben Lorentzen's groups resolved the crystal structure of IFT80, showed for the first time that is dimerised and defined the protein domains responsible for this. This sheds light on higher-order protein complex formation within intraflagellar transport machinery. |
| Impact | Original research article in revision at Elife. |
| Start Year | 2017 |
| Description | Work experience for A-level students |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | I provided an afternoon hands-on workshop for A-level work experience pupils, who were visiting the research facility for a week. The work experience program was open to students from under-privileged areas in greater London. Together we did fluorescent microscopy, and the students were able to observe a number of cellular structures, including cilia. I also presented them some of my most recent data. They were keen to ask questions about higher education, career options and about the science itself. |
| Year(s) Of Engagement Activity | 2017 |