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High Throughput Phenotypic Screening for Drug Discovery in Male Fertility/Infertility


Project Description

Infertility is a significant global problem affecting ~1 in 7, or ~80 million couples (Barratt et al., 2017). Although the causes of infertility are heterogeneous, male factor is now the leading cause and accounts for at least 50% of cases and although asthenozoospermia (poor/dysfunctional sperm motility) is the commonest disorder in this population yet there is no drug a man can take, nor that can be added to his sperm in vitro, to improve fertility (Martins da Silva et al., 2017). Couples instead rely on Artificial Reproduction Technology (ART), such as IVF and ICSI, which is expensive, invasive and not without risk. Despite this, year-on-year, ART is increasingly utilized worldwide. There is clearly an unmet need for the development of alternate treatment strategies for male factor infertility, and a demand for focussed treatment options to improve sperm motility (Barratt et al., 2018).

A fundamental hurdle to development of new drugs, either for male fertility or contraceptive use, is the lack of appropriate assay systems to allow rapid screening of large and diverse pharma libraries (Marins da Silva et al., 2017). The challenge of the unique size, shape and motility of spermatozoa has instead resulted in current strategies based on direct assessment of sperm motility and function, which until recently has not been feasible in the context of a drug discovery programme due to the prohibitive costs of time and resources (Martins da Silva et al., 2017).

We (Andrews/Barratt) have developed a high throughput phenotypic screening platform for measuring both human sperm motility and acrosome reaction using the industry-standard robotic systems available at the National Phenotypic Screening Centre (http://npsc.ac.uk/). This is a unique cutting-edge platform that was originally developed to screen compound libraries to identify potential contraceptive agents. However, in this project we will be studying the use of this approach to identify potential sperm enhancing compounds from a series of different libraries (e.g. approved drugs/bioactives and large chemical diversity sets). The project will then focus on characterising in greater depth the mode-of-action of lead compounds and perform experiments to determine cellular targets. We will use this preliminary data to present to both industrial and non-industrial funding sources to facilitate translation of these potential compounds to the clinic. The project will be an unrivalled opportunity for a student to learn a raft of advance biological techniques as well as gain hands-on experience with industry-standard drug discovery.

Apply
To apply please send a cover letter, curriculum vitae and two references to:

Funding Notes

Please note this is a self-funded PhD project

References

Barratt CLR, De Jonge CJ and Sharpe RM. ‘Man Up’: The importance and strategy for placing male reproductive health centre stage in the political and research agenda. Human Reproduction. Published advanced access 08/2/18.
Barratt CLR, Björndahl L, De Jonge CJ, Lamb DJ, Osorio Martini F, McLachlan R, Oates RD, van der Poel S, St John B, Sigman M, Sokol R, Tournaye H. The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities. Hum Reprod Update. 2017 Nov 1;23(6):660-680.
Brown SG, Costello S, Kelly MC, Ramalingam M, Drew E, Publicover SJ, Barratt CLR, Da Silva SM. Complex CatSper-dependent and independent [Ca2+]i signalling in human spermatozoa induced by follicular fluid. Hum Reprod. 2017 Oct 1;32(10):1995-2006.
Martins da Silva SJ, Brown SG, Sutton K, King LV, Ruso H, Gray DW, Wyatt PG, Kelly MC, Barratt CLR, Hope AG. Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem. Hum Reprod. 2017 May 1;32(5):974-984.

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