Functional Genomic Analysis Of The Role Of P53 In Early Embryo Death After Assisted Reproductive Technologies (ART).
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Assisted reproductive technologies (ART, such as IVF and related techniques) are successful treatments for most forms of infertility. ART are expensive therapies and much of this cost is related to the relative inefficiency of the technology. Much of this is due to the high mortality of the resulting embryos. Typically, 45-80% of embryos produced by ART do not survive the first week. Consequently the chance of any individual embryo resulting in a successful birth is not high. There has been only ....Assisted reproductive technologies (ART, such as IVF and related techniques) are successful treatments for most forms of infertility. ART are expensive therapies and much of this cost is related to the relative inefficiency of the technology. Much of this is due to the high mortality of the resulting embryos. Typically, 45-80% of embryos produced by ART do not survive the first week. Consequently the chance of any individual embryo resulting in a successful birth is not high. There has been only modest increments in embryo survival in recent years. The low cahnce of individual embryos resulting in a baby means that: (1) generally several treatment cycles are required; (2) superovulation is used to maximise the number of embryos produced giving an accumulation of unwanted cryopreserved embryos; (3) more than one embryo is generally transferred resulting in a significant incidence of multiple pregancies. The high mortality of the early embryo seems to be a general feature of IVF but its causes and effectors are not known. It has recently been established that it largely occurs due to a form of cell 'suicide' known as apoptosis. This form of cell death has important normal functions: its activation allows for cells that are no longer required to be removed, allowing the remodelling of tissues and it also serves to remove cells that are irreversibly damaged. p53 is a protein that has the ability to 'sense' cell stress and damage and to direct the cell to undergo apoptosis if the stress is severe. This project will examine if ART cause increased expression of p53 and whether this elevation of p53 causes embryonic cell death. We will examine the factirs that control p53 expression in the embryo. using mice with mutations that stop the function of p53 and several of its regulatory proteins. Experiments will determine the susceptibility of embryos possessing these mutations and will therefore allow us to define the proteins causing apoptosis after ART.Read moreRead less
The Formation And Development Of The Ovarian Follicular Membrana Granulosa
Funder
National Health and Medical Research Council
Funding Amount
$351,575.00
Summary
In order for the ovary to be able to release eggs and produce hormones such as oestrogen, follicles must grow within the ovary. Each follicle contains one egg and when the follicle is large and filled with fluid it can rupture, releasing the fluid and egg in the process of ovulation. A key part of the structure of the follicle is a non-cellular layer called the basal lamina. This basal lamina encapsulates the inner cells, the egg and the fluid in the follicle. Each women has millions of follicle ....In order for the ovary to be able to release eggs and produce hormones such as oestrogen, follicles must grow within the ovary. Each follicle contains one egg and when the follicle is large and filled with fluid it can rupture, releasing the fluid and egg in the process of ovulation. A key part of the structure of the follicle is a non-cellular layer called the basal lamina. This basal lamina encapsulates the inner cells, the egg and the fluid in the follicle. Each women has millions of follicles prior to her birth, ten of thousands in her reproductive years, and none at the menopause. Since she only ovulates about 500 in her lifetime most follicles die in the process of growing to ovulatory size. This project will examine the structure of the follicle wall and the cells that make up that wall. How these cells replicate during follicle growth has never been discovered. This research has important implications for the many women who have polycystic ovarian disease, whose follicles fail to grow to full size. We will be examining these ovaries directly. The research also has importance in the next phase of IVF developments.Read moreRead less
This project aims to study how the two main hormones, FSH and testosterone, control the development and production of sperm throughout adult life. In previous NHMRC-supported research we were the first to overturn the long-standing belief that FSH was vital to the start of sperm production in all warm-blooded animals. This insight was achieved from experiments using a genetically modified strain of mouse. We used this mouse strain to develop a new experimental paradigm to provide unique insight ....This project aims to study how the two main hormones, FSH and testosterone, control the development and production of sperm throughout adult life. In previous NHMRC-supported research we were the first to overturn the long-standing belief that FSH was vital to the start of sperm production in all warm-blooded animals. This insight was achieved from experiments using a genetically modified strain of mouse. We used this mouse strain to develop a new experimental paradigm to provide unique insight into how hormones start up and support sperm production. In this present proposal we wish to take this research further. Although we have shown that FSH is not vital to the startup or continuing of sperm production, we believe it still does have an important role in causing the growth of a large enough population of Sertoli cells of the testis. These highly specialised cells have the unique job to support, nourish and coordinate the production of sperm. Sertoli cells are known to be the only target in the body for FSH and so that FSH must act upon them exclusively. We believe this occurs almost solely during early life - starting before birth and into early infancy - well before adult life when sperm are produced for the first time. In this way these processes being studied determine the size of mature testis. Our new approaches to studying the question of how the two main hormones control sperm production involve developing new types of genetically modified mice which have extra and exclusive FSH activity as well as some new research methods to be applied to understanding how FSH acts on the Sertoli cell using techniques derived from gene therapy and from cell transplantation. This research has the possibility to uncover new causes of previously unexplained male infertility (the majority having no known cause so far), to help develop better hormonal male contraceptives, and to quetion the need for expensive treatments for some infertile men.Read moreRead less