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Pre-clinical testing of new therapeutic treatments for cystic kidney disease


About This PhD Project

Project Description

The primary cilium on the ventral surface of most vertebrate cells acts as an “antennae” that receives and transduces chemo- and mechanosensory signals. Cilia regulate the Shh and Wnt developmental signalling pathways, and cilia in the epithelial cells of kidney tubules act as fluid sensors to regulate tubule growth. Defects in the primary cilium cause many forms of cystic kidney disease including the most common form, polycystic kidney disease. Patients require renal replacement therapy (dialysis and transplantation) as a result of cystic kidney disease that leads to kidney failure. However, there are currently no preventative treatments or new therapeutic interventions that modify disease progression or the long-term outlook of patients with these conditions.

We have recently completed a series of cell-based screens of existing drugs and clinical development compounds for effects on cilia formation and function. These have used high-throughput siRNA knockdown and high-content imaging to identify a series of candidate hit compounds (comprising nine drugs already approved for therapeutic use, two novel benzylimidazole compounds and 11 other clinical development compounds). This project will investigate if hit compounds can be “repurposed” for treatment or amelioration cystic kidney diseases by testing in vitro and in vivo cytotoxicity, efficacy and specificity. We will use cellular models (siRNA and inducible shRNA knockdowns, isogenic CRISPR-Cas9 knock-out cell-lines, and 3D renal cultures of epithelial spheroids). We will also use limited testing in preclinical animal models to determine if the best-scoring hits can rescue pronephric cyst formation in zebrafish embryo models. In parallel, we will use these approaches to define a hit series of “druggable” small molecule derivatives of our most promising clinical development hit compounds, in order to define preliminary structure activity relationships.

The overall objective of the research is the identification of drug hits that could be re-purposed as potential treatments of cystic kidney diseases. In addition, the basis of a more extensive validation programme for new lead compounds is likely to be established by this research. This pathway should enable the future rational design of therapeutics to prevent disease progression and for possible treatment of cystic kidney diseases.

Environment:
The student will be based in the section of Ophthalmology and Neuroscience (OPNE), School of Medicine, University Of Leeds. This project will provide research training in a wide range of cell biology and medicinal chemistry techniques including siRNA/shRNA gene knockdown, cell culture, lentiviral transduction, high content imaging, immunofluorescence microscopy, western blotting, and drug efficacy and cytoxicity assays.

Eligibility:
This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidate whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

How to apply
Applications can be made at any time. To formal apply for this project applicants should complete a Faculty Application form using the link below http://medhealth.leeds.ac.uk/download/4087/fmh_scholarship_application_form_2018_19 and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School at

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to

Any queries regarding the application process should be directed to .

Potential applicants are welcome to contact Prof Colin Johnson at with informal enquiries about this research project.

References

1. Slaats GG, et al. (2015). Screen-based identification and validation of four novel ion channels as regulators of renal ciliogenesis. J. Cell Sci. 128: 4550-9
2. Wheway G, et al. (2015). An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell. Biol. 17: 1074-87.

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