How is The Smith Lab utilising Biotechnology?

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Our current work is focussed upon dissecting the genetics underpinning androgen production, androgen signaling and the impacts these processes have on male health and reproduction. To do so, we have utilised the Cre/loxP recombination system to generate mouse models with disruptions in androgen production either ubiquitously or in a cell-specific manner. Alongside this, we have further utilise the Cre/loxP technology to generate novel cell-specific ablation models, permitting the ablation of cells crucial for testicular function at critical points of testicular development and in adulthood. Using these transgenic models has permitted a number of novel findings including the identification of extended roles for the Sertoli cells in the testis and never before described mechanisms for androgens and its receptor in adrenal function and maintenance. Alongside this, we have also utilised cutting edge biotechnologies and omics approaches to further our studies investigating androgens and their significant roles in both development and adult reproductive function and health. Together, our investigations will aim to exploit these technologies further for the development of bespoke novel therapeutics and for the development of innovative in vivo clinical models, relevant to the millions of people worldwide experiencing reproductive and endocrine disorders.

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What clinical problems are The Smith Lab addressing with this knowledge?

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Specifically, the biotechnologies currently being developed and utilised in our lab include those capable of delivering transgenics to specific cell types in vivo such as viral vectors and nanoparticle technologies. By focussing upon these systems, the group aims to develop methods of modifying gene expression in specific cell types of the endocrine system, namely those found in the adrenals and the testis, through the delivery of transgenes capable of silencing gene expression (such as miRNAs and shRNAs) as well as gene-editing technologies such as CRISPR/Cas. These systems are able to be delivered at any relevant time point and can be further exploited for the investigation of novel therapeutics including the delivery of pharmaceuticals to specific cell types in vivo and the development of “gene therapy” technology for the treatment of male reproductive disorders and for addressing the current need for a long-lasting male contraceptives.

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The schematic above depicts one way in which this technology could be utilised. A male with reproductive disorders would present at a clinic:

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• next-generation sequencing performed to find possible mutations

• a mouse model created with edited genes to mimic the patient's mutations

• if a genetic mutation or phenotype can be confirmed this technique could then be utilised to deliver targeted therapy

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How will this investigation help the problem?

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To complement our extensive studies in vivo, our group has also extended our studies into the development of the novel in vitro models of the endocrine system using cutting edge 3D bioprinting techniques. In doing so, we aim to model the complex paracrine and endocrine signaling systems required for testis and adrenal function, permitting not only further investigations into the mechanisms underpinning androgen production but also providing a ‘test bed’ for any potential novel therapeutics being developed for the treatment of male reproductive disorders.

Finally, both our innovative transgenic models of endocrine dysfunction and our in vitro models of function endocrine organs will be complemented using cutting edge omics analysis techniques including RNA-seq and proteomic analysis, permitting an in-depth investigation into the genetics and the mechanisms underpinning male endocrine and reproductive disorders, an area in which knowledge is currently limited.

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