Role Of The T-box Transcription Factors, Tbx5 And Tbx20, In Cardiac Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$345,000.00
Summary
Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling dev ....Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling development of the heart in the embryo. Examples are Tbx5, a member of the T-box family of transcription factor genes mutated in Holt Oram syndrome, and Nkx2-5, a homeodomain transcription factor gene mutated in families with hole in the heart and cardiac electrical defects. We propose to investigate the involvement of a new member of the T-box gene family, Tbx20, in cardiac development and disease, and to compare and contrast its function with that of Tbx5. The Tbx5 and Tbx20 proteins interact directly with Nkx2-5 to stimulate transcription of cardiac genes, making Tbx20 a good candidate for involvement in inherited disease. We will use gene targeting technology to delete the Tbx20 gene in mice, and will analyse heart anatomy, gene expression and function to determine the effect of its loss. We will also investigate how Tbx20 interacts with other cardiac regulatory pathways, by crossing Tbx20 mutant mice with mice deficient for Nkx2-5 and Tbx5, strains that show heart abnormalities similar to those found in human patients. Microarray technology, which examines gene expression on a whole genome scale, will also be used to identify genes that are regulated by these transcription factors. Finally, we will search for mutations in the Tbx20 gene in human patients that have inherited heart abnormalities. In doing so we may improve our understanding of disease causation and predisposition thereby identifying patients at risk and providing improved genetic counselling and diagnosis.Read moreRead less
Control Of Blood Vessel Development By SOX Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Cardiovascular disease is Australia s greatest health problem, with an estimated 3 million Australians suffering a spectrum of conditions from hypertension through to heart failure. Improper development of blood vessels in the embryo can compromise survival of the embryo, and predispose patients to vascular disease after birth. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fu ....Cardiovascular disease is Australia s greatest health problem, with an estimated 3 million Australians suffering a spectrum of conditions from hypertension through to heart failure. Improper development of blood vessels in the embryo can compromise survival of the embryo, and predispose patients to vascular disease after birth. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fundamental importance in the health sciences to gain an understanding of how blood vessels form and regenerate. We discovered a gene, Sox18, that appears to regulate blood vessel development by controlling the formation and-or properties of endothelial cells, which line the blood vessels and make them impermeable. Our research so far indicates that MICE WITH DEFECTS IN SOX18 DIE FROM VASCULAR DEFECTS, underlining the importance of this gene. THIS PROJECT IS CONCERNED WITH FINDING OUT HOW SOX18 WORKS - exactly what goes wrong in mice lacking this gene, whether Sox18 can influence endothelial cell behaviour in cell culture, how Sox18 comes to be active in endothelial cells, what genes are switched on by Sox18, and what genes Sox18 co-operates with in its role in endothelial cells. The answers to these questions will not only provide fundamental basic information about how blood vessels development is controlled, but also sow the seeds for possible future therapies in which blood vessel development could be stimulated (eg in wound healing) or suppressed (eg in tumour progression) by drug treatments.Read moreRead less
I am a developmental biologist investigating the molecular mechanisms regulating prenatal development and stem cell populations in the adult. I am studying defects in essential developmental processes leading to severe congenital disorders such as mental
The Role Of Crim1, A Novel TGFb Superfamily Modulator, In Early Vertebrate Patterning, Vascular And Renal Development.
Funder
National Health and Medical Research Council
Funding Amount
$501,300.00
Summary
The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be dele ....The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be deleterious, with their overexpression leading to conditions such as renal fibrosis and cataract. The activity of these growth factors is regulated by many other proteins, including protein antagonists which bind and inactivate them. It is therefore possible that by understanding these antagonists, we can find new ways of altering TGF beta superfamily activity. We have previously identified a novel protein, Crim1, which we have now shown can bind to TGF superfamily members and can reduce their secretion. We believe that Crim1 plays a role in the patterning of the central nervous system, the development of the blood vessels and the kidneys by regulating the TGFbeta superfamily. In this grant we will be investigating what the effect of disruption to Crim1 is on these organ systems and working out which members of the TGFbeta superfamily it is affecting to cause these effects. To do this, we will knock out the gene in zebrafish and characterise the defects found in a mouse line in which the gene has been disrupted. This may be important in developing new ways of activating or inactiviating these growth factors in a number of clinical conditions.Read moreRead less
Signalling And Transcriptional Activity For Craniofacial Morphogenesis In An Experimental Genetic Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$74,755.00
Summary
Abnormalities in craniofacial development affect 2-1000 births in Australia. The aim of this project is to identify genes crucial for the development of the head and face. In particular the project focuses on the Twist1 gene. TWIST1 plays a key role in craniofacial development and individuals lacking functional Twist1display facial anomalies such as craniosynostosis and cleft palate. Dissecting the function of Twist1 is essential to identifying new avenues for the prevention of these defects.