Identification And Characterisation Of Genes Required For Cardiac Morphogenesis
Funder
National Health and Medical Research Council
Funding Amount
$434,706.00
Summary
The heart is the first organ to become functional as an embryo forms, reflecting its critical role in sustaining life. Mistakes that occur as the heart develops have devastating consequences for an individualĂs survival and health. We have identified two zebrafish mutants with heart defects and, using sophisticated imaging and genetic studies, will investigate these defects and identify the genes responsible. This research will improve our understanding of correct and diseased heart formation.
Identifying The Critical Pathways Which Regulate Vertebrate Craniofacial Development
Funder
National Health and Medical Research Council
Funding Amount
$552,131.00
Summary
Understanding the genes which underlie human birth defects is of immense clinical importance. Our laboratory is a world-leader investigating a gene responsible for facial skeleton development, Grhl2. With our wide range of models, we will discover how Grhl2 works to ensure the face and skull develop properly during birth.
Investigating The Genetic Cause Of Genital Abnormalities In Males
Funder
National Health and Medical Research Council
Funding Amount
$299,564.00
Summary
This project investigates the genetic cause of a relatively common defect in male genitalia, hypospadias, in which the penis opening is aberrantly located. Hypospadias affects 1 in ~250 males, usually requires surgery and can cause problems with intercourse and urination. Using new technologies to study patient DNA, we will identify mutations causing hypospadias and new genes involved in development of the male genitalia. This will lead to improved clinical diagnosis and management of patients.
A Novel Gene Family Implicated In Neural Crest And Craniofacial Malformation
Funder
National Health and Medical Research Council
Funding Amount
$695,016.00
Summary
We have identified a new type of receptor that when defective causes facial clefting in animal models. We are using our unique laboratory and clinical resources to understand how these birth defects occur and to investigate the molecular signalling events that are controlled by this olfactory receptor. These studies will pave the way to designing pharmaceuticals that may eventually ameliorate or even stop this major group of birth defects.
Defining The Genetic Causes Of The Abnormal Vertebral Segmentation Syndrome, Spondylocostal Dysostosis
Funder
National Health and Medical Research Council
Funding Amount
$476,523.00
Summary
There are many birth defects that cause vertebral malformations along the spinal column. These occur as the embryo develops in utero, during the formation of structures known as somites. Somites also form the ribs, muscle, tendons and dermis. We are studying an example of this type of birth defect called spondylocostal dysostosis (SCD). We have shown that mutations in three different genes cause some cases of this inherited disease in humans. These genes are called DLL3, MESP2 and LFNG. However, ....There are many birth defects that cause vertebral malformations along the spinal column. These occur as the embryo develops in utero, during the formation of structures known as somites. Somites also form the ribs, muscle, tendons and dermis. We are studying an example of this type of birth defect called spondylocostal dysostosis (SCD). We have shown that mutations in three different genes cause some cases of this inherited disease in humans. These genes are called DLL3, MESP2 and LFNG. However, 80% of SCD patients do not have a mutation in any of these genes. Thus we need to discover how these other cases occur. This project uses two strategies in parallel. Firstly, we will analyse large families that have a history of SCD, and use this information to find causative gene mutations. However, a significant proportion of cases occur without family history. To find out what genes are involved in these cases is more difficult. We have created a mutant mouse by specifically deleting the DLL3 gene. This mouse has very similar vertebral malformations to SCD. We will compare embryos from normal and mutant mice to find genes that do not operate normally in the mutant. These genes are candidates for causing SCD, and thus we will screen these genes in human patients for mutations. However, simply finding a change in a candidate gene does not necessarily mean that this is the cause of SCD. To prove this, we have developed several tests to determine if the mutation alters the normal function of the protein encoded by the mutated gene. This work will greatly benefit the future genetic assessment of SCD patients. In addition, by studying our mouse model of SCD, we will gain a greater understanding of how DLL3 functions. This knowledge may be useful in developing stem cell-based therapies that involve the production of specific cell types.Read moreRead less
Understanding How Placental Development Is Affected By Cellular Hypoxia And Cited2, A Hypoxia-responsive Gene.
Funder
National Health and Medical Research Council
Funding Amount
$352,500.00
Summary
During pregnancy the mammalian fetus depends entirely on its mother for nutrition and oxygen, and to remove waste products. These are exchanged in the placenta, where the blood supplies of the mother and fetus come into close proximity. The placenta is connected to the mother via blood vessels in the uteruine wall, and to the fetus via the umbilical cord. This organ is also involved in making hormones necessary for mammary gland development, suppression of the local immune system to prevent feta ....During pregnancy the mammalian fetus depends entirely on its mother for nutrition and oxygen, and to remove waste products. These are exchanged in the placenta, where the blood supplies of the mother and fetus come into close proximity. The placenta is connected to the mother via blood vessels in the uteruine wall, and to the fetus via the umbilical cord. This organ is also involved in making hormones necessary for mammary gland development, suppression of the local immune system to prevent fetal rejection, and production of progesterone required to maintain the pregnancy. Thus failure of correct placenta formation can be associated with a range of complications of human pregnancy, such as missed abortion, miscarriage, intrauterine growth restriction, and pre-eclampsia. The exact cause of these complications is unknown, but by studying mouse models with placental defects we hope to address these issues. Many of the common diseases in society, such as heart attack, stroke and pre-eclampsia, are either directly or indirectly the result of an organ being deprived of oxygen (termed hypoxia). Mammals respond to hypoxia in several different ways to deliver more oxygen to the affected area, such as increasing numbers of oxygen-carrying red blood cells, enlarging existing blood vessels, and making new vessels. Many of the genes involved in this process are known, and one of these is called Cited2. Paradoxically, during gestation hypoxia is crucial for the normal formation of many fetal organs and their blood supply, including the placenta. We have created a mutant mouse by specifically deleting the Cited2 gene. Mutant mouse embryos die during gestation and do not form a fully functional placenta. We will examine these defective placentas in order to understand how this organ needs Cited2 to form. Since the Cited2 gene is turned on by hypoxia, this will also allow us to see if the placental defects are caused by a failure of the normal response to hypoxia.Read moreRead less
Birth defects are present in 3% of live births and account for some of the 78% of fetuses lost before birth. The causes of these defects are largely unknown. Some are due to genetic factors, some to environmental stresses, and others to a combination of genetic and environmental influences on fetal development. This research aims to identify the genetic and environmental factors that cause birth defects with the anticipation that the occurrence of birth defects may be reduced.
Determining The Causes Of Congenital Vertebral Defects
Funder
National Health and Medical Research Council
Funding Amount
$956,136.00
Summary
Many birth defects cause vertebral malformations along the spinal column. These originate as the fetus forms, and we have previously shown that some of these are caused by gene mutation and/or environmental factors during gestation. However, the origins of many such defects remain unexplained. We will examine the DNA of a large number of patients to find more genes causing such defects. We will also test if these new genes predispose a fetus to being more susceptible to environmental influences.
Developmental Genetics And Stem Cell Biology Of Birth Defects And Cell Based Therapy
Funder
National Health and Medical Research Council
Funding Amount
$823,008.00
Summary
Professor Tam is a mammalian embryologist studying the genetic and cellular mechanisms that form and shape the embryo and its organs during development. His work will help us to understand the causes of birth defects, how to prevent them and to correct the disorders by stem cell-based therapy.
From Endoderm To Gut: Regulation Of Lineage Allocation And Morphogenesis In The Murine Embryo
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
One of the most critical steps in early development is the generation of the full complement of cell types required to build the embryo. A thorough understanding of the mechanisms underlying this is vital for the development of methods for directing the differentiation of stem cells for use in regenerative medicine. The objective of our research is to understand the cellular and molecular mechanisms underlying the assignment of cells to particular fates and the establishment of the body plan of ....One of the most critical steps in early development is the generation of the full complement of cell types required to build the embryo. A thorough understanding of the mechanisms underlying this is vital for the development of methods for directing the differentiation of stem cells for use in regenerative medicine. The objective of our research is to understand the cellular and molecular mechanisms underlying the assignment of cells to particular fates and the establishment of the body plan of the embryo. The endodermal cell layer forms the lining of the embryonic gut which gives rise to the entire gastrointestinal tract, the respiratory tract and other structures including the liver and the pancreas during organogenesis. This investigation focuses on the questions of how the pluripotent progenitor cells are allocated to the endodermal lineage and how the embryonic gut is patterned during early development of the mouse embryo. Analysis of endoderm development will provide insights into the roles of the allocation of progenitor cells to tissue lineages, cell movement, and diversification and maturation of functional cell types. These processes are universally relevant to the formation of all types of organ primordia in the embryo. Understanding the complexity of tissue interactions and the interplay of molecular mechanisms of cell lineage choice and differentiation in the embryo is a major challenge. However, knowledge of the processes that drive tissue differentiation in the embryo is absolutely crucial for enhancing our ability to direct cell and tissue differentiation for the realization of cell-based technologies in biomedicine.Read moreRead less