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
Hormonal Control Of Serotli Cell Maturation And Function
Funder
National Health and Medical Research Council
Funding Amount
$512,898.00
Summary
This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR ac ....This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR activity within Sertoli cells is essential for 'induction' of complete sperm development. Ongoing work will develop unique 'inducible' transgenic models that will allow, for the first time, selective analysis of Sertoli AR in both 'developing' and 'adult' testes. Our innovative models will allow AR function to be switched on or off at any stage of development, providing unique opportunity to determine the key AR-regulated factors and pathways controlling induction, maintenance or restoration of sperm production. In past NHMRC research we created a novel transgenic model to study another major reproductive hormone, FSH. Using the hormone-deficient background of 'hpg' mice, we found that androgen and FSH act synergistically in the developing 'meiotic' germ cells that form sperm. Using the latest microarray gene technology we generated datasets of androgen-regulated genes with or without FSH activity, which combined with our unique transgenic AR and FSH models, will be used to identify key pathways, including those enhanced by androgen-FSH synergism, in the early testicular response. Our research will provide new knowledge of the precise roles and pathways of testicular AR actions, to ultimately identify key genetic and regulatory factors as targets for significantly improved therapy for male infertility, gonadal tumours, or contraception.Read moreRead less
The Sertoli Cell: Master Regulator Of Hormone-induced Spermatogenic Development
Funder
National Health and Medical Research Council
Funding Amount
$563,536.00
Summary
This project will determine the key roles of major hormones (testosterone, follicle-stimulating hormone, Vitamin A) in Sertoli cells, unique highly specialised cells found in the testis that provide essential nutritional and structural support for sperm production. This research will provide new understanding of the biological pathways controlling sperm development, leading to new molecular targets for infertility or cancer treatment or diagnosis, or new contraceptive strategies for men.
Epigenetic Regulation Of Cell Lineage Differentiation In The Early Embryo
Funder
National Health and Medical Research Council
Funding Amount
$440,983.00
Summary
Exposure of embryos to a range of stresses can increase the predisposition to chronic diseases of adulthood. Stressing embryos at critical stages of development cause errors in reorganization of the nucleus that are required for normal gene expression. These errors are propagated into adulthood. This project will map the normal processes of nuclear reorganization and define how stress to the embryo changes this process, allowing an understanding of the causes of some important chronic diseases.
HtrA4-induced Endothelial Dysfunction In Early-onset Preeclampsia
Funder
National Health and Medical Research Council
Funding Amount
$86,073.00
Summary
Preeclampsia (PE), a life-threatening disorder of pregnancy, is characterized by a sudden increase in blood pressure in association with wide-spread endothelial dysfunction. Placenta-derived factors are believed to cause PE development. Our recent studies have identified that HtrA4, a placenta-specific serine protease may contribute to endothelial dysfunction. This study will investigate the mechanisms of HtrA4-induced endothelial dysfunction.
Epigenetic Reprogramming Within The Pluripotent Lineage Of The Early Embryo
Funder
National Health and Medical Research Council
Funding Amount
$663,050.00
Summary
Cells of the early embryo have the remarkable capacity to form all of the different tissues and organs in the body. This property requires re-organisation of the embryo’s genetic material in a manner analogous to re-booting a computer. This project will define the properties of this rebooting process. This information will allow much better strategies for building spare parts for regenerative medicine and provide the information required to reduce the incidence of inborn defects.
Advancing maternal age is associated with the progressive loss of fertility, increased miscarriage and a greater risk of bearing children with birth defects. These adverse reproductive outcomes result, in part, from the loss of egg quality with age. We aim to identify and characterise genes involved in the age-related decline in egg quality. The long-term goal of this research is to develop novel strategies to improve fertility outcomes for women who chose to delay pregnancy until later in life.
Interstitially Invasive Trophoblast Of The Murine Placenta: Developmental Origins, Functions And Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$369,717.00
Summary
Due to the obvious limitations to studying human pregnancy, the mouse has become a valuable model. However, invasion of the placenta into the uterine wall and vasculature, critical for successful pregnancy, is poorly understood in the mouse. The aims of the proposal are designed to gain a better understanding of these processes in mice and will provide a more accurate model system to study serious pregnancy complications resulting from abnormal placental invasion, such as preeclampsia.