Why is The Smith Lab investigating the adrenal?

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The adrenal plays an important role in many physiological processes; to be effective in doing so it needs to tightly regulate and renew its zones to deal with the changing demand for steroid production. Cortex zones have the ability to reversibly expand, contract and alter biochemical processes to accommodate needs and maintain homeostasis. The adrenal cortex is a dynamic tissue due to its replacement of senescent cells with newly differentiated cells from the outer adrenal cortex.

 

A number of studies have provided insight into the processes of cortex renewal and have revealed that the regulation of adrenal zonation is much more complex than the current paradigm describes, however, the mechanisms controlling this still aren’t clearly understood.

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What is The Smith Lab doing to develop understanding?

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Experiments conducted as early as 1937 by Deansley and Parkes demonstrated the impacts of androgens on the adrenal cortex. They first demonstrated the regression of the mouse X-zone, thought to give rise to the adult adrenal cortex, in untreated males during puberty and the redevelopment following castration. Furthermore, it has been shown that treatment with androgenic compounds shortly after birth and in response to castration prevented the development of an X-zone. These studies highlighted that the control of this region was potentially andromimetic. Despite this early identification of androgen action on the X-zone and adrenal cortex, the mechanism is still not understood and experiments dissecting this have not expanded on the issue much in recent years.

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Androgens are known to be an essential regulator of male health. Androgen receptor (AR) is widely expressed throughout the adrenal cortex, yet the wider role for androgen signaling in the adrenal remained underexplored. This is thought to be due to the limitations of mouse models when investigating adrenal androgens as the rodent’s adrenal does not produce androgens.

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How will this investigation help the problem?

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Ongoing research in the Smith Lab aims to generate novel mouse models in which to dissect the role of autocrine and paracrine regulation of the adrenal by androgens. This work began with the generation of an adrenal specific androgen receptor knockout mouse model. Through this, we can demonstrate that androgen signaling is required to facilitate X-zone regression, cell clearance and to protect against adrenal degeneration during aging. Although this work provides invaluable insight into the regulation of the adrenal cortex by androgens we want to expand on this to make the androgen profile of the mouse more in line with what is observed in the human. We are currently in the process of developing adrenal specific nanobiotechnology to achieve this, with the prospect of generating novel mouse models to investigate polycystic ovarian syndrome (PCOS), prostate cancer and adrenarche. Furthermore, we aim to use this technology for adrenal disease treatment for conditions such as Cushing’s syndrome and congenital adrenal hyperplasia (CAH).

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