Prof Harvey is a cardiac developmental biologist working on the molecular and anatomical basis of heart development and congenital heart disease, and of pluripotency and regenerative potential in adult cardiac stem cells.
Identifying The Pathological Mechanism Of Polyalanine Expansion Mutations In The X-linked Hypopituitarism Gene SOX3
Funder
National Health and Medical Research Council
Funding Amount
$402,846.00
Summary
Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituita ....Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituitary has failed to form completely, these babies are extremely ill and in some instances do not survive. We have previously shown that XH is due to an unusual change in the SOX3 gene in which the number of consecutive alanine residues is increased above a critical threshold (polyalanine expansion mutations). Similar mutations have recently been identified in several other genes that also cause severe birth defects. However, little is currently known about how polyalanine expansion mutations cause these disorders. The overall aim of this proposal is generate a mouse model for this disorder. Analysis of these mice will help us to answer many unresolved questions about this disorder including: How does the mutant protein cause this disorder? Which parts of the brain and pituitary are affected and how is their function altered? How does the mutant protein affect other genes and proteins in the cell? Ultimately, we hope that this mouse model will help us to develop new and improved therapies for XH and other disorders that are caused by alanine expansion mutations.Read moreRead less
Identification Of Genes Regulating Vertebrate Intestinal Development
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Colorectal cancer (CRC) causes 14 per cent of all cancer deaths in Australia. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities (mutation ....Colorectal cancer (CRC) causes 14 per cent of all cancer deaths in Australia. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a lifetime. Together the mutated genes produce changes in cell behaviour in processes such as growth, migration, angiogenesis (the ability to attract a blood supply) and cell death. All of these processes are active during normal development of a vertebrate organism, but are generally shutdown in the adult state, except in cancer. In this study, we propose to identify a set of genes that control the development of the intestine in a small tropical fish, the zebrafish. Zebrafish are vertebrate organisms, closely related to mice and man. Essentially all the pathways regulating development are conserved in the three species. The zebrafish offers several advantages: they are small, easy to breed, cheap to maintain and, most importantly, their embryos are transparent, making it possible to visualise development in live embryos in a simple microscope. Our project will use a panel of mutant strains of zebrafish that have an array of visible abnormalities in intestinal development. The abnormalities were induced using a chemical that produces single base pair changes in DNA. An established technique called positional cloning will allow us to identify the genes in which the mutations have been introduced, and provide a genetic explanation for the intestinal abnormalities. Upon identification of the mutated genes, our ultimate aim will be to test whether they also play a role in the development of CRC, using mouse models and human tissues.Read moreRead less
Normal embryonic and foetal devlopment depends on the ability of cells to move from one place to another. This behaviour enables cells to be produced at one site and transported to one or a number of other sites. Although the face appears to us as a single seamless unit it originates as a number of blocks of tissue which begin development separately and must grow in a coordinated way that enables them to meet at precisely the correct time, in the correct place and in the correct order. The basis ....Normal embryonic and foetal devlopment depends on the ability of cells to move from one place to another. This behaviour enables cells to be produced at one site and transported to one or a number of other sites. Although the face appears to us as a single seamless unit it originates as a number of blocks of tissue which begin development separately and must grow in a coordinated way that enables them to meet at precisely the correct time, in the correct place and in the correct order. The basis of this growth and fusion is the ability of individual cells to move around the embryo to supply the raw materials for this construction process when and where they are needed. The combined activities of the cells in constructing the various parts of the embryo is known as morphogenesis which literally means creating shape. We are trying to gain insight into the basis of morphogenesis that produces the face. This is important because the face and other structures that are closely associated with it are particularly prone to errors. Despite this, surprisingly little is known about the mechansims that control development of the face. We know a great deal about which cells are involved in constructing the face but very little about what triggers the initial steps of development or maintains ordered growth. Our research is aimed at defining genes that are important in controlling development of the face through the study of normal development and birth defects. We are defining the function of genes that appear to be important in controlling the behaviour of cells during early development of the face. This knowledge will assist in understanding the control mechanism for facial devlopment and will eventually lead to improvements in the treatment and prevention of birth defects affecting these structures.Read moreRead less