This program will expand research and policy development to overcome androgen misuse (off label testosterone prescribing for invalid indications) and combat androgen ('anabolic steroid') abuse for performance and image enhancement. Beyond expanding ongoing research, it will develop a new focus in developing drugs to accelerate recovery from androgen abuse, thereby preventing relapse during the slow natural recovery period typically lasting 6-18 months or longer
The Mechanism Of Spermatid Differentiation - A Link To Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$506,425.00
Summary
To discover novel regulators of male fertility, we have screened libraries of mutant mice generated by a chemical mutagen. This project aims to define the function of the mutated gene identified in a male-specific infertile mutant mouse line. The mutated gene has been proposed to play a role in regulating cell death and suppress lung tumour formation. Our data may reveal novel options for male infertility treatment and for the development of male contraception and lung cancer biomarkers.
I am a reproductive biologist working to define key mechanisms for sperm development and function; and by extension the causes of human male infertility.
Male fertility requires sufficient production of healthy sperm in the testis. This project builds on our discovery that testicular cells communicate via the wnt family of proteins during sperm development, and that interruption of their activities reduces fertility in mice. We propose to use mouse models to study the precise steps in sperm production affected by Wnt signalling and how it works.
Toll-like Receptor And MyD88 Signalling In The Testis
Funder
National Health and Medical Research Council
Funding Amount
$498,411.00
Summary
Infertility affects one in seven couples desiring children. A proportion (5-10%) of the male partners in these couples have immunological reactions against their own sperm. The testes, where sperm are made, and the immune system normally exist in a balanced, beneficial relationship, but sometimes this relationship goes wrong. This can also lead to chronic pain and increased risk of testicular cancer. The project investigates this relationship in order to provide assistance for these men and thei ....Infertility affects one in seven couples desiring children. A proportion (5-10%) of the male partners in these couples have immunological reactions against their own sperm. The testes, where sperm are made, and the immune system normally exist in a balanced, beneficial relationship, but sometimes this relationship goes wrong. This can also lead to chronic pain and increased risk of testicular cancer. The project investigates this relationship in order to provide assistance for these men and their partners.Read moreRead less
This project aims to study the hormonal control of Sertoli cell development and function. In the testis, these highly specialised cells provide essential nutritional and structural support for sperm production. In current NHMRC-supported research we created a unique mouse model to study the individual roles of two key reproductive hormones FSH and testosterone in spermatogenesis. This novel approach involved the selective expression of transgenic FSH on the hormone-deficient background of hpg mi ....This project aims to study the hormonal control of Sertoli cell development and function. In the testis, these highly specialised cells provide essential nutritional and structural support for sperm production. In current NHMRC-supported research we created a unique mouse model to study the individual roles of two key reproductive hormones FSH and testosterone in spermatogenesis. This novel approach involved the selective expression of transgenic FSH on the hormone-deficient background of hpg mice, which normally lack both androgens and FSH. Our analysis revealed that FSH provided the main stimulation for Sertoli cell and early germ cell proliferation, whereas FSH required testosterone for later stages of sperm formation. In this proposal we now plan to investigate FSH and the changing steroidal contributions during the critical postnatal stage of Sertoli cell development. We will study individual of combined actions of FSH and steroids, including the controversial role of estradiol in Sertoli and germ cell function, which may all have profound consequences on sperm production and male fertility. We will also establish unique mouse models to address fundamental questions about the mechanisms of androgen actions in the testis, and the requirement for androgen receptor expression in Sertoli and neighbouring peritubular cells for the overall testosterone response. Furthermore, we will use new microarray gene screening technology to identify the FSH- and androgen-regulated gene pathways during Sertoli cell proliferation. This research has relevance to the controversial view of environmental steroids affecting human testicular development and reducing sperm counts, and offers the potential to uncover new causes of previously unexplained male infertility or testicular cancers, and to help develop better strategies for hormonal male contraceptives, and treatments for male infertitliy or cancer.Read moreRead less
A Role For Epigenetic Modifiers In Maintaining Chromosome Integrity During Passage Through The Male Gamete In The Mouse.
Funder
National Health and Medical Research Council
Funding Amount
$390,541.00
Summary
There is a high level of infertility in the human population, the majority of which remains unexplained. 15% of married couples in the United States are affected by infertility and it is estimated that the male partner is responsible for half of this. Some of this infertility is familial indicating an underlying genetic cause. An increased understanding of the underlying genes involved, should lead to improvements in treatment. The mouse, with its ability to produce large numbers of offspring an ....There is a high level of infertility in the human population, the majority of which remains unexplained. 15% of married couples in the United States are affected by infertility and it is estimated that the male partner is responsible for half of this. Some of this infertility is familial indicating an underlying genetic cause. An increased understanding of the underlying genes involved, should lead to improvements in treatment. The mouse, with its ability to produce large numbers of offspring and its ability to be genetically modified, provides an excellent model system for studying the genetic contribution to reproductive fitness. The studies outlined in this application aim to determine whether a group of genes, previously identified as a result of their effects on epigenetic gene silencing, are also involved in reproductive fitness in the mouse. Our hypothesis is that these genes encode proteins required for normal pairing and segregation of chromosomes during male gametogenesis. While none of the experiments described here involve studies on humans, the genes identified are likely to have human homologues. It will, then, be relatively simple to discover whether infertile men carry mutations in these genes. Assisted reproductive technologies (ART) now accounts for between 1% and 3% of annual births in many western countries and IVF services continue to grow. While these procedures provide an effective treatment for many infertile couples, they promote the transmission of any underlying genetic defects to the next generation. These genetic defects, therefore, need to be identified and understood. Recently it has been reported that the frequency of some rare diseases are, indeed, higher in ART offspring. Furthermore, if our hypothesis is correct and some of the genes involved are critical for chromosome integrity, then mutations in these genes may also increase the risk of cancer later in life.Read moreRead less
A man's reproductive health and fertility is affected by processes that occur long before adulthood. The testis and sperm precursor cells first form in the fetus and then grow until the time of puberty, when the upper limit for sperm production is set. This project studies how one key signaling molecule, activin, helps establish normal testicular architecture and drives maturation of sperm precursor cells, and how it contributes to aberrent function in men with testicular cancer.
I am a cell biologist investigating how cells in the developing testis communicate to set the stage for normal sperm production in the adult. My studies address what goes wrong in certain clinical conditions including testicular cancer, and our findings a
ATR-X Syndrome: Role Of ATRX In Testicular Growth And Spermatogenesis
Funder
National Health and Medical Research Council
Funding Amount
$650,881.00
Summary
Infertility is surprisingly common and affects 1 in 20 Australian men. Testosterone and its receptor, the androgen receptor, are well known to be essential for spermatogenesis and fertility. We have identified an important regulator protein (ATRX) of androgen receptor activity and show that loss of function of ATRX in testes of mice leads to spermatogenesis defects. Identifying the molecular action of ATRX will lead to a better understanding of the underlying causes of infertility in men.