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
This research program entitled Stem cells from the testis is designed to use cutting edge molecular and cellular biology techniques to isolate adult stem cells from the testis. These stem cells will be expanded in cell culture and tested for therapeutic activity in mouse models of infertility, leukaemia and kidney failure. The knowledge and techniques developed in the mouse system may help unlock the potential of human cell based therapies for these and other degenerative diseases.
Cell Cycle Regulation By The Epidermal Growth Factor Receptor
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The rate of growth and death of normal cells is regulated through signals transmitted from the cell surface to the nucleus. In many human cancers the normal regulatory mechanisms are subverted, leading to uncontrolled growth of the cells. We aim to characterize the signals that are initiated by binding of the Epidermal Growth Factor (EGF) to its receptor and to understand how these signals influence the ability of the cell to divide and to survive. We will identify the pathways that contribute t ....The rate of growth and death of normal cells is regulated through signals transmitted from the cell surface to the nucleus. In many human cancers the normal regulatory mechanisms are subverted, leading to uncontrolled growth of the cells. We aim to characterize the signals that are initiated by binding of the Epidermal Growth Factor (EGF) to its receptor and to understand how these signals influence the ability of the cell to divide and to survive. We will identify the pathways that contribute to uncontrolled growth in tumor cells. This knowledge is necessary for the design of new therapies targetted to the molecular lesions which stimulate solid tumors.Read moreRead less
The Regulation Of Pluripotency And Self-renewal In Embryonic And Germline Stem Cells.
Funder
National Health and Medical Research Council
Funding Amount
$491,767.00
Summary
Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell based therapies promises to revolutionize the treatment of many common human diseases. For instance, in neurodegenerative conditions such as Parkinsons disease, normal ....Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell based therapies promises to revolutionize the treatment of many common human diseases. For instance, in neurodegenerative conditions such as Parkinsons disease, normal embryonic stem cells grown in culture could be used to replace the lost or disabled neurons in the patient. Many other conditions including diabetes, cystic fibrosis, myocardial infarction (heart attack) and stroke could potentially be treated with stem cell based therapies. Understanding the molecular regulators that govern establishment and maintenance in culture of stem cell lines derived from embryos and from germ cells is the primary goal of this study. We will use well-established techniques to genetically manipulate mouse embryonic stem cells and embryos to examine the role of a specific gene, NANOG. Named after the Celtic legend of Tir NaNog (land of the ever young). When NANOG was forced to remain active, embryonic stem cells were able to grow in media deficient in factors usually required for self-renewal and did not lose their pluripotency even when treated with chemical agents that usually induce differentiation. Understanding the full capacity of NANOG to influence stem cell self-renewal and elucidation of the underlying molecular pathways regulated by this gene will provide valuable insights into the establishment and manipulation of stem cell lines from embryonic and adult tissues.Read moreRead less
Liver damage after liver surgery or shock is called ischemia-reperfusion injury (IRI). Recovery after surgical removal of liver tissue is due to liver regeneration. IRI and liver regeneration are controlled by specialised proteins called cytokines, one of which, TRAIL, is essential for both IRI and liver regeneration. This research is to find out how TRAIL exerts such seemingly opposite effects. The aim is to learn how to protect the liver against damage, and to stimulate its recovery.