Professor Lee Smith
Research focus, background, recent progress, funding support.
Professor Lee Smith’s group focus upon all aspects of male reproductive health, specialising in identifying genetic and hormonal control signals that support male fertility and steroid hormone (testosterone) production
Latest News from the Smith Group!
July 2016: Our paper on Modelling the structure and dynamics of biological pathways, is accepted for publication in PLoS Biology!
May 2016: We’ve been awarded a grant from the Wellcome Trust’s Institutional Startegic Support Fund (ISSF) to further explore vascular androgen signalling in males!
May 2016: A new first! Two papers accepted for publication in the space of 45 minutes.
Some fantastic media coverage of our new collaborative paper in Scientific Reports which shows that androgens influence vascular calcification, a possible explanation for the increased risk of cardiovascular disease seen in men!
April 2016: Lee received the 2016 Young Andrologist Award at the American Society of Andrology meeting in New Orleans
March 2016: Many congratulations to our PhD student Anne-Louise Gannon on winning a New Investigator Award at the 17th Adrenal Cortex conference in Boston USA!
December 2015: I am very honoured to have been invited by the MRC to join their Population and Systems Medicine Board, from February 2016.
November 2015: Our review of cell ablation models in the testis has made the front cover of Andrology
October 2015: I am incredibly honoured to have been named the American Society for Andrology’s Young Andrologist of the year for 2016!
October 2015: We’ve been awarded a £500,000 BBSRC project grant to continue our work on androgens and pituitary function!
October 2015: Our Andrology review article describing how testicular cell ablation models have contributed to our understanding of testis development and function is now available!
September 2015: Our article using Lentiviral delivered transgenes to knockout genes in the adult testis has made the front cover of Molecular Reproduction and Development.
July 2015: Our >£2M 5-year Programme Grant is to be funded by the MRC from 2016-2021!
June 2015: Two more papers, one in PLoS Genetics and one in Molecular Reproduction and Development are now available!
May 2015: Our new paper with Dr Rod Mitchell is published in Science Translational Medicine.
The adult testis is essentially a factory, which produces two key products, – the synthesis and secretion of steroid hormones, notably testosterone (made by testicular Leydig cells), and the production of mature sperm from spermatogonial stem cells (a process known as spermatogenesis). My group is working both to understand how these processes are regulated, and to develop new mechanisms to support both male fertility and life-long health and wellbeing.
Development of functional sperm from stem cells within the testis is a complex process. The genes that control this in men remain largely uncharacterised because it is very difficult to identify them. Our group use mouse models of male infertility to identify genes essential for sperm production. Through this process we are developing an understanding of the genetic networks and processes underlying testis function; knowledge that will be of benefit both to development of future treatments for male infertility and development of non-hormonal male contraceptives.
Steroidogenesis – testosterone production
In the male, androgens (such as testosterone) play significant roles both in male development and in adult reproductive function and general health. A reduction in androgen action during key stages of development results in incomplete physical masculinisation which can have life-long impacts (fetal programming), whilst disruption in androgen action in adulthood can lead to infertility, and has also been linked to several other widespread chronic conditions such as cardiovascular disease, obesity, depression and age-related deterioration in health.
It has been known for many years that testosterone signalling plays an essential role in regulating the process of spermatogenesis. However how this signal impacts upon each testicular cell-type has remained elusive. Testosterone acts by binding to the androgen receptor (AR) a single copy gene located on the X-chromosome which is expressed in several cell-types of the testis, but not germ cells (sperm). Thus testosterone’s effect upon sperm development must be indirect, acting via the supporting cell-types.
We have used the Cre/lox Recombination system to generate mouse models with selective ablation of AR from every somatic (supporting) cell-type of the testis. Our extensive analyses have characterized a previously undescribed paracrine-signalling network within the testis, which acts to support both sperm production and testosterone production. 'Good planning and serendipity: exploiting the Cre/Lox system' in the testis on PubMed.
Our current work is focused upon dissecting the mechanisms underlying this, using novel transgenic mouse models coupled to a wide variety of cutting edge molecular genetic and endocrinological techniques. In addition to this, we have extended our studies to investigate mouse models with targeted deletion of AR in the other body systems, including the cardiovascular system, adipose tissue and prostate.
Together, these investigations highlight a body-wide and lifelong role for androgen-signalling in supporting lifelong health and wellbeing in men. Our future focus is now on understanding how androgen production is controlled within the testis and how this influences not only male fertility, but also other important clinical problems such as cardiovascular disease, diabetes, and age-related conditions.
We are grateful for continuing support from the MRC, BBSRC, British heart Foundation and Michelson.