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.
Exposing The Mechanisms Underlying Mammalian Meiotic Onset
Funder
National Health and Medical Research Council
Funding Amount
$536,563.00
Summary
Germ cells must undergo a special form of cell division, meiosis, before they can form oocytes in females or sperm in males. We want to know, in detail, how meiosis is triggered in germ cells and what the first steps are in meiotic progression. This information will help us understand the causative factors in infertility (1 in 6 couples of reproductive age are infertile), control fertility (develop new contraceptives) and avoid testicular cancer (the most common tumour type in young men).
This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics - the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells - the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
Role Of The Histone Variant H3.3 In Germ Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$581,223.00
Summary
Over their life cycle, germ cells are unique in undergoing a large scale reformatting of their gene or DNA control systems, required for their own development, and for the development of the fertilized egg. We think that the protein ïhistone H3.3Í is crucial to this reformatting process. We will test this possibility by determining how much H3.3 is present in germ cells. Also, we will make mice which lack this protein in germ cells to see if this affects the reformatting process.
Molecular Regulation Of Pluripotency In The Mammalian Germline
Funder
National Health and Medical Research Council
Funding Amount
$611,935.00
Summary
Germ cells generate sperm in males or oocytes in females. In males, germ cell numbers are tightly controlled in the embryo, with too few germ cells causing infertility, and unrestrained germ cell numbers leading to testicular cancer. We have discovered a molecular mechanism that regulates germ cells in the embryo, and propose to study in mice how this regulation is accomplished and the consequences of defective regulation, in order to learn more about how infertility and testis cancer arise.
The Role Of Y Chromosome Genes In Male Infertility
Funder
National Health and Medical Research Council
Funding Amount
$323,164.00
Summary
Infertility carries an enormous personal and financial burden to the Australian community, with about one in eight couples of reproductive age considered infertile. Male factors contribute to about half of all infertility, although the genetic causes remain largely unknown. The goal of this research proposal is to identify the genetic basis of male diseases, particularly infertility, to improve the clinical management of infertility.
Disorders Of Gonadal Development: Molecular Approaches To Improved Patient Care
Funder
National Health and Medical Research Council
Funding Amount
$863,413.00
Summary
We will use new genomic technologies to identify the genetic causes of disorders of sex development (DSD), a common and often distressing class of birth defect. Knowing the molecular lesion will take the guesswork out of diagnosis and treatment of DSD children. We will also exploit a new discovery to develop new means of rapid, cost-effective, non-invasive diagnosis and therapy for testicular cancer, the commonest form of cancer in men under 30.
Nodal Signalling In Male Germ Cell Development: Balancing Fertility And Testicular Cancer Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$536,595.00
Summary
Testicular cancer is the most common type of cancer in men aged 20-40 years, and its incidence has doubled in the last 30 years. It is sometimes fetal and often results in infertility. We have discovered new genes that regulate testicular cell behaviour in the developing fetus, and here test the concept that defects in these genes might disrupt cell behaviour to the point where cancers form during adult life. Outcomes may lead to new ways to diagnose and treat testicular cancers.
My research is to learn more of the genetic and epigenetic mechanisms governing the development of the reproductive cell lineage, or the cells that make eggs and sperm. My research is required to better understand human reproduction and human embryonic, fetal and neonatal development, and will help in the treatment of diseases affecting these processes.
Adult and embryonic stem cells have enormous therapeutic potential. Haemopoietic stem cells have been the most intensely studied and widely used in a therapeutic setting, yet we have only a patchy knowledge of the genes required for their proliferation and survival. I will use classical genetic screens in the mouse to identify genes that regulate stem cell behaviour. I will analyse two existing mutant mouse strains with reduced numbers of haemopoietic stem cells, and execute a novel genetic scre ....Adult and embryonic stem cells have enormous therapeutic potential. Haemopoietic stem cells have been the most intensely studied and widely used in a therapeutic setting, yet we have only a patchy knowledge of the genes required for their proliferation and survival. I will use classical genetic screens in the mouse to identify genes that regulate stem cell behaviour. I will analyse two existing mutant mouse strains with reduced numbers of haemopoietic stem cells, and execute a novel genetic screen utilising mice with a defect in the self-renewal of adult haemopoietic and neural stem cells, to find mice with a recovered stem cell compartment.Read moreRead less