Hormonal Responsive Coding And Non-coding Genes In Penile Differentiation And Hypospadias
Funder
National Health and Medical Research Council
Funding Amount
$835,182.00
Summary
Hypospadias, a failure of the correct formation of the penis, is the second-most common birth defect, occurring in around 1% of boys. It causes distress to both newborn and parents, requiring surgical intervention, and is a burden of cost and is a risk to the child. Furthermore, it is frequently associated with other abnormalities. We have a novel model in which we can induce penis abnormalities and define the link between hormonal exposures and defective penis differentiation.
Endogenous Oestrogen Is A Key Missing Link In Urethral Hypospadias
Funder
National Health and Medical Research Council
Funding Amount
$456,467.00
Summary
Defects in penis development are among the most common birth abnormalities, and affect around 1 in every 150 live male births in Australia. Development of the penis is known to be driven by male hormones (androgens), but we have recently shown that oestrogen also plays a role in this process. This project will define the role of estrogen in penis development and how a loss or gain of estrogens can cause developmental defects.
Hypospadias, is a common defect, in which the urethra opens abnormally along the shaft of the penis not at the tip. It affects 1 in every 125 boys born in Victoria each year. However, the cause(s) of over two-thirds of these cases cannot be explained. Our studies using marsupials show that this process is mediated by a hormone (5alpha-androstanediol), with previously undetermined physiological function. This study will provide novel data on the interactions of the genes and hormones that result ....Hypospadias, is a common defect, in which the urethra opens abnormally along the shaft of the penis not at the tip. It affects 1 in every 125 boys born in Victoria each year. However, the cause(s) of over two-thirds of these cases cannot be explained. Our studies using marsupials show that this process is mediated by a hormone (5alpha-androstanediol), with previously undetermined physiological function. This study will provide novel data on the interactions of the genes and hormones that result in defects of penile development.Read moreRead less
Hypospadias is one of the most common developmental defects in humans, yet over two thirds of the cases cannot be explained. Our recent studies using marsupials show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. This study will provide novel data on the interactions of the genes and hormones that will inform our understanding of this common developmental defect of male development
Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes is hindered because in most mammals virilisation occurs in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar ....Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes is hindered because in most mammals virilisation occurs in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies and rabbits, to test 3 hypotheses about 5-alpha-androstanediol and specific enzymes in the developing reproductive tissues that either convert this hormone to active and inactive forms. The results of these experiments will direct testing for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilisation (pseudohemaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohemaphroditism of unknown aetiology in humans.Read moreRead less
New Models For The Onset Of Virilisation In The Developing Male
Funder
National Health and Medical Research Council
Funding Amount
$405,750.00
Summary
Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes are hindered because in most mammals virilisation occurs in utero, in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments us ....Impairment of virilisation is one of the most common developmental defects in humans, yet over half the cases cannot be explained by our current knowledge. Studies of these processes are hindered because in most mammals virilisation occurs in utero, in the early fetus. Our recent studies using marsupials, where virilisation occurs after birth show that this process is mediated by 5-alpha-androstanediol, a hormone with previously undetermined physiological function. We will conduct experiments using tammar wallabies, to test hypotheses that explain why different male tissues - such as the reproductive ducts, prostate and penis - start to differentiate at widely different times. We will investigate pathways of androgen formation and the activation and inactivation of hormones in the target organs, and the role of hormone binding proteins. We will also investigate the role of growth factors that may mediate growth of the penis during early development. The results of these experiments will direct funding in subsequent years to test for corresponding gene mutations in our collection of over 200 specimens from patients with defects of virilization (pseudohermaphroditism) whose causes are still unknown. It is our expectation that the findings in these studies will provide insight not only into the pathways by which testicular hormones masculinize the developing male, but will also explain instances of male pseudohermaphroditism of unknown aetiology in humans.Read moreRead less
Characterising The Role Of MID1 In X-linked Opitz Syndrome: Implications For CATCH22 And Related Disorders
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Opitz syndrome is a debilitating genetic disorder which affects the normal development of many organs and tissues of the human embryo. Patients with Opitz syndrome commonly present with facial deformities (such as cleft lip and palate) as well as both genital and heart defects. Males are usually more severely affected than females although the severity of the disease can vary even amongst males of the same family. Patients can die suddenly in infancy or suffer further developmental impairment du ....Opitz syndrome is a debilitating genetic disorder which affects the normal development of many organs and tissues of the human embryo. Patients with Opitz syndrome commonly present with facial deformities (such as cleft lip and palate) as well as both genital and heart defects. Males are usually more severely affected than females although the severity of the disease can vary even amongst males of the same family. Patients can die suddenly in infancy or suffer further developmental impairment due to respiratory complications and swallowing difficulties that result from the significant facial deformities. A brighter outlook for patients is expected if early and often repeated surgical repair is undertaken to correct not only the facial deformities but also any heart and genital abnormalities. Our research laboratory has recently identified the gene that, when mutated, causes one form of Opitz syndrome. Defects in this gene account for around half the cases with the disorder. Evidence suggests that there may be a number of other genes involved in causing the remaining cases of the disease. The proposed research is aimed at investigating the molecular and developmental mechanisms that go awry as a result of the gene mutation. It is anticipated that these studies will provide valuable scientific knowledge about why some patients are more severely affected than others as well as offering clues to the identity of the genes that cause the remaining cases of Opitz syndrome. The results also have potentially important implications for the understanding of other diseases that show similar deformities. The knowledge gained from this research is expected to provide a valuable aid for effective genetic counselling (as well as the option of prenatal diagnosis) for families at risk of further affected pregnancies. This will also ultimately lead to more effective disease management and correction in the affected child.Read moreRead less