Developmental Functions Of A Novel Zinc-finger Protein
Funder
National Health and Medical Research Council
Funding Amount
$666,812.00
Summary
Diseases of the respiratory track and the immune system represent major public health burdens, from the common cold and lung cancer, to increased risk of infections and auto-immune diseases. We have identified a new gene that is essential for lung development, and required for normal development of antibody-producing immune cells. Here we want to define the mechanism by which this gene functions, in order to better understand how lungs and immune cells develop.
Functional Analysis Of Candidate Sex-determining And Gonadal Development Genes
Funder
National Health and Medical Research Council
Funding Amount
$503,500.00
Summary
This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together, as well as how genetic defects can lead to disorders of sexual development. Def ....This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together, as well as how genetic defects can lead to disorders of sexual development. Defects in sexual development in the human embryo not only result in some of the most common forms of birth defects but also have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects will lead to improved patient management.Read moreRead less
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
Defects in sexual development in the human embryo result in some of the most common forms of birth defects, which have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects may lead to improved counseling and perhaps also therapeutic possibilities. This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper d ....Defects in sexual development in the human embryo result in some of the most common forms of birth defects, which have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects may lead to improved counseling and perhaps also therapeutic possibilities. This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together.Read moreRead less
Control Of Salvador-Warts-Hippo Pathway Activity In Drosophila And Mammals
Funder
National Health and Medical Research Council
Funding Amount
$514,048.00
Summary
The primary function of the Salvador-Warts-Hippo (SWH) pathway is to dictate the appropriate size of organs in developing animals. Deregulation of this pathway results in vastly overgrown organs and can lead to the formation of cancer in humans. Our study will provide important insights into how the size of organs are controlled during development by identifying new SWH pathway components. We will also increase understanding of diseases that arise due to aberrant tissue growth, such as cancer.
Hedgehog Signalling In Limb And Craniofacial Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$494,544.00
Summary
Anomalies of the face and limbs are amongst the most common features of human birth defects, and their frequent association suggests that the same genes are involved in governing the development of the limbs and face during embryogenesis. We have used a genomics-based approach to identify genes involved in limb development based on their alteration in a mouse model which develops extra fingers and toes. Defects in this mouse result from changes in Gli3, a gene which is known to be important in b ....Anomalies of the face and limbs are amongst the most common features of human birth defects, and their frequent association suggests that the same genes are involved in governing the development of the limbs and face during embryogenesis. We have used a genomics-based approach to identify genes involved in limb development based on their alteration in a mouse model which develops extra fingers and toes. Defects in this mouse result from changes in Gli3, a gene which is known to be important in both limb and face development. Based on the organs in which our genes of interest are active, we believe that they will also play key roles in embryonic development of the limbs, face and other organs. We now plan to investigate the regulation of a subset of these genes based on analysis in mouse models of limb and face development. In addition, we have chosen to further analyse the function of a completely novel gene we have identified which our preliminary studies suggest may play a role in the normal development of the lip and palate. These studies have the potential to shed light on the processes governing how organs develop, as well as on the molecular basis of common birth defects such as polydactyly (extra fingers and toes) and cleft palate.Read moreRead less
The Regulation Of Pleiotropic Responses By Phospho-Ser/Tyr Binary Switches Embedded In Growth Factor Receptors
Funder
National Health and Medical Research Council
Funding Amount
$349,190.00
Summary
Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors ....Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors) on the surface of cells which in turn activate signalling cascades that convey messages within the cell instructing a specific response. We have identified a new mechanism that allows a growth factor receptor to convert analogue inputs (in the form of growth factor stimulation) to a digital output (where a cell responds in a decisive fashion). This analogue-to-digital conversion is encoded by a molecular switch embedded in growth factor receptors that toggles between two alternate positions to promote either cell survival alone or cell survival as well as cell differentiation-proliferation. In this manner, these molecular switches have binary (either-or) characteristics and provide a new explanation for the independent regulation and coordination of different cell functions. These findings have implications for understanding how specific cellular responses such as cell survival, proliferation and differentiation can be regulated and perhaps harnessed to improve tissue regeneration after damage (e.g. in stroke, heart attack trauma) or in understanding how things go wrong in diseases such as cancer where cell survival, proliferation and differentiation become deregulatedRead moreRead less