Postnatal Germ Cells Are Controlled By FSH During 'minipuberty' At 3-6 Months, And Deranged By Cryptorchidism To Cause Seminoma And Infertility
Funder
National Health and Medical Research Council
Funding Amount
$813,739.00
Summary
This study will investigate the exciting possibility that the risk of cancer and infertility in adulthood in infants born with undescended testes might be obviated by understanding how primitive sperm cells behave in the postnatal testis. The study will define the key changes to the primitive sperm cells, including their timing and control by hormones, so surgery is done at the right time +/-accessory hormone treatment to optimise future sperm function for babies with undescended testes.
The Cause Of Undescended Testis And Inguinal Hernia
Funder
National Health and Medical Research Council
Funding Amount
$743,848.00
Summary
This study aims to define in both animal models and children how the testis descends from the abdomen to scrotum, and how undescended testis and inguinal hernia are likely to be caused by defects in the same, very indirect signalling pathway. The results will demonstrate where to look for genetic causes and proof of principle for possible future medical treatments for the 3 commonest major operations in children for congenital and acquired undescended testis and inguinal hernia.
Germ Cell Development In The Postnatal Testis: The Key To Early Surgery To Prevent Infertility And Malignancy In Cryptorchidism
Funder
National Health and Medical Research Council
Funding Amount
$725,326.00
Summary
The germ cells have been studied very extensively before birth or after puberty, but little is known about what happens shortly after birth. In children with undescended testes, early germ cell development is deranged, and this may be the key to find the right time for surgery to prevent subsequent infertility and risk of cancer. This project proposes some novel hypotheses to explain this and the studies aim to obtain the evidence to support surgery in the first 3-6 months of life..
This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in children of undescended testes. Our long-term aims is to find a non-surgical treatment for undescended testes, and these studies will significantly aid in that goal. We will look at a completely new testicular hormone as well as a molecule released from nerves to determine their exact role in the mechanism. This project should allow us to understand finally one of the unresolved puzz ....This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in children of undescended testes. Our long-term aims is to find a non-surgical treatment for undescended testes, and these studies will significantly aid in that goal. We will look at a completely new testicular hormone as well as a molecule released from nerves to determine their exact role in the mechanism. This project should allow us to understand finally one of the unresolved puzzles of the anatomical differences between males and females.Read moreRead less
Growth Factors And Regulatory Genes Controlling Male Spermatogonial Proliferation And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$354,536.00
Summary
In newborn and prepubertal boys the testis contains germ cells which are at a premature stage of development and very suseptible to degeneration especially if the testes fail to descend to the scrotum. The molecules which are responsible for the health of these germ cells have been unknown and only recently the way has been opened for direct study of these factors. This has been made possible by a new assay, developed in our labarotory, in which we can grow these germ cells under defined conditi ....In newborn and prepubertal boys the testis contains germ cells which are at a premature stage of development and very suseptible to degeneration especially if the testes fail to descend to the scrotum. The molecules which are responsible for the health of these germ cells have been unknown and only recently the way has been opened for direct study of these factors. This has been made possible by a new assay, developed in our labarotory, in which we can grow these germ cells under defined conditions. This step forward has highlighted some areas of knowledge which need further research such as identification of the processes which stimulate gonocytes to grow and divide. We need to test growth factors, somatic cell factors and also isolate new genes which are associated with germ cells and their growth. This knowledge will have outcomes in two major areas. First, the new findings could be applied to treatment of infertility resulting from undescended testes in which a stimulus could be given to make the germ cells grow again. Second, work in developing longer term culture of germ cells coupled with introduction of mutations will enable us to make mutant mice with a specific gene abnormality, similar to transgenic or gene knockout mice. This technological development would prove less expensive and time consuming with more reproducible and direct outcomes. Mutant mouse technology is a powerful tool to determine the effects of individual genes in the whole animal (mouse).Read moreRead less
The Genitofemoral Nerve And Gubernaculum In Testicular Descent And Inguinal Hernia
Funder
National Health and Medical Research Council
Funding Amount
$339,750.00
Summary
This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in infant boys of undescended testes. In addition, the tunnel through the abdominal wall which permits testicular descent very commonly fails to close afterwards, allowing the intestines to protrude through the hole to cause an inguinal hernia, which is a tender lump in the groin,and requires surgery to resolve. Our long-term aim is to understand testicular descent and inguinal closure ....This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in infant boys of undescended testes. In addition, the tunnel through the abdominal wall which permits testicular descent very commonly fails to close afterwards, allowing the intestines to protrude through the hole to cause an inguinal hernia, which is a tender lump in the groin,and requires surgery to resolve. Our long-term aim is to understand testicular descent and inguinal closure well enough to develop non-surgical treatments for these two conditions, which are the two commonest abnormalities in children requiring surgery. We will examine how male hormones control descent of the testis indirectly by altering the anatomy and function of a specific nerve suplying the groin and scrotum. A simple and safe treatment that avoided surgery would be a major advance for infants in the developing world.Read moreRead less
The Structural Basis Of The Interaction Of Insulin-like Peptide 3, A Key Regulator Of Fertility, With Its Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
The hormone, insulin-like peptide 3, has recently been shown to act directly on male and female germ cells to cause their maturation. It has considerable promise as a therapeutic agent for the regulation of fertility. Drugs based on the peptide may be used to assist in cases of infertility, and drugs that block its action have great potential as male and female contraceptives. Towards these goals, our project aims to understand how this peptide exerts its unique biological effects.
The Limb Bud As A Model For Gubernacular Migration During Inguinoscrotal Testicular Descent.
Funder
National Health and Medical Research Council
Funding Amount
$439,073.00
Summary
This project examines the mechanism of descent of the testes from its original position inside the abdomen of the fetus to the scrotum in baby boys. When this process is abnormal, it leads to the common anomaly of undescended testes. Tha ultimate aim is to understand the process well enough to consider nonoperative treatment. The study will look at the tip of the gubernaculum, the ligament that anchors the testis to the groin early in development, and how it develops a growing tip that elongates ....This project examines the mechanism of descent of the testes from its original position inside the abdomen of the fetus to the scrotum in baby boys. When this process is abnormal, it leads to the common anomaly of undescended testes. Tha ultimate aim is to understand the process well enough to consider nonoperative treatment. The study will look at the tip of the gubernaculum, the ligament that anchors the testis to the groin early in development, and how it develops a growing tip that elongates towards the scrotum. The project will examine the factors controlling this process as well as the embryological mechanism involved.Read moreRead less
Structure-function And Domain Minimization Of Insulin-like Peptide 3, A Novel Member Of The Insulin Superfamily.
Funder
National Health and Medical Research Council
Funding Amount
$288,000.00
Summary
Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selectio ....Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selection. More recent evidence shows that the peptide has clear roles in modulating male and female germ cell maturation. These effects indicate that agonists and antagonists of INSL3 have potential as specific drugs for novel contraceptive approaches or infertility treatments in both sexes. The actions of INSL3 are mediated by interaction with a G-protein coupled receptor known as LGR8. This receptor is expressed in the testes and ovary as well as several other tissues including the brain. However, very little is known about how INSL3 interacts with LGR8 to produce its physiological responses. Consequently, we will determine the structural features of the peptide that are responsible for receptor binding. This will be achieved by use of chemical peptide synthesis of not only INSL3 but also of analogues of the peptide that contain modified residues or domains. These will be assayed for characteristic INSL3 activity and the results, together with those acquired by modern biomolecular interaction analyses, will be used to identify the receptor binding regions for INSL3. This information, together with a determination of the three-dimensional structure of INSL3 by using NMR spectroscopy, will then be disseminated using computer-assisted molecular modelling to design smaller, more stable, orally active analogues. Such mimetics of reduced size that are correspondingly cheaper and simpler to prepare and handle will have great potential for therapeutic regulators of human fertility.Read moreRead less