I am a developmental biologist who identifies and characterises genes required for normal embryonic development in mouse. I translate this information into the genetic diagnosis and developmental understanding of congenital malformations in humans.
Role Of Homeobox Gene Nkx2-5 In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$227,340.00
Summary
This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then con ....This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then control expression of a host of genes required for muscle differentiation and the development of form (morphogenesis). Mutations in one copy of the human Nkx2-5 gene have recently been discovered to be associated with atrial septal defect, or Ohole in the heartO, a sometimes serious inherited defect in heart structure. Mouse embryos with a mutation in both copies of the gene have a much more serious defect in ventricle formation that is incompatible with life. The studies are designed to extend our understanding of the genetic regulation of chamber formation in the heart. We will firstly make a mouse model of the human disease using gene targeting technology, which allows us to make precise alteration in single genes in this animal. Secondly, we will apply new technology to the heart that will let us visualise molecular and cellular events at higher resolution. This technology, which uses fluorescent tags on cells and a laser to measure cell identity, has been used to great affect in the field of immunology, but can be adapted to the heart. We will use it to isolate and characterise the precious early cells that give rise to the heart in the embryo. It is in these cells that the human and mouse mutations have their first effects. Our studies have relevance to understanding and screening for human inherited heart abnormalities, and for understanding the general principles of heart formation that may reveal valuable ways to intervene in heart disease.Read moreRead less
Patched Gene Family Control Of Epidermal Development And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
The skin is the largest organ in the body and functions as a barrier against infection and dehydration. From a clinical perspective we need to know how to regenerate skin for better wound healing and the treatment of burns. We have identified a genetic pathway that regulates the stem cells of the skin and this research will show us the mechanism whereby the skin develops and regenerates, as well as the possible manipulations we can use to increase healing in the clinic.
The Role Of Patched/Hedgehog Signalling In Common Human Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Mutations in the patched -hedgehog pathway are responsible for most of the common skin cancer basal cell carcinoma and some of the brain tumour medulloblastoma. Despite this knowledge we still do not know which cell in the skin gives rise to the basal cell carcinoma, and which cell in the brain gives rise to medulloblastoma. This application describes an approach using animal models to answer these questions and therefore further our understanding of how a normal cell becomes a tumour cell. In a ....Mutations in the patched -hedgehog pathway are responsible for most of the common skin cancer basal cell carcinoma and some of the brain tumour medulloblastoma. Despite this knowledge we still do not know which cell in the skin gives rise to the basal cell carcinoma, and which cell in the brain gives rise to medulloblastoma. This application describes an approach using animal models to answer these questions and therefore further our understanding of how a normal cell becomes a tumour cell. In addition this proposal extends out current studies to examine new gene family members in large tumour collections.Read moreRead less
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
Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulat ....Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulation of a key copper pump, the Menkes protein, which helps control copper levels in the body and we are using the genetic advantages of the fruit fly Drosophila to discover new genes that regulate Menkes activity and therefore copper levels. These studies could lead to novel therapies for a range of copper-related disorders.Read moreRead less
The Role Of Transcriptional Co-activators And Co-repressors During Embryonic Development
Funder
National Health and Medical Research Council
Funding Amount
$82,421.00
Summary
Every creature starts out as a single fertilized egg. The genome directs the embryonic development of the egg by regulating the expression of genes each of which must be turned on or off at the correct time and place. This essential balance between the activation or repression of genes is controlled by groups of proteins, including ‘transcriptional co-activators’ and ‘repressors’. This project aims to better understand the role of these proteins during embryonic development.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0347245
Funder
Australian Research Council
Funding Amount
$630,000.00
Summary
Functional Genomics Analysis - linking a multicentred facility. The aim of this project is to enhance and network the functions and activities of the Clive and Vera Ramaciotti Centre for Gene Function Analysis (CGRCGFA), a joint venture that services five major universities in the Sydney-Newcastle area. This application is for equipment that will improve the speed of DNA analyses, and for a laboratory information management system that will standardise the handling of data and sample information ....Functional Genomics Analysis - linking a multicentred facility. The aim of this project is to enhance and network the functions and activities of the Clive and Vera Ramaciotti Centre for Gene Function Analysis (CGRCGFA), a joint venture that services five major universities in the Sydney-Newcastle area. This application is for equipment that will improve the speed of DNA analyses, and for a laboratory information management system that will standardise the handling of data and sample information at all nodes of the CVRCGFA.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0232455
Funder
Australian Research Council
Funding Amount
$545,000.00
Summary
The Molecular Analysis of Variation and Gene Function. The aim of this project is to establish the nodes of the Clive and Vera Ramaciotti Centre for Gene Function Analysis (CVRCGFA) which is a joint venture that serves the five major universities and three Institutes in the Sydney-Newcastle region. The primary focus of this application is to create new facilities at the hubs of CVRCFGA that are integral to the analysis of molecular variation in a range of organisms. The study of molecular vari ....The Molecular Analysis of Variation and Gene Function. The aim of this project is to establish the nodes of the Clive and Vera Ramaciotti Centre for Gene Function Analysis (CVRCGFA) which is a joint venture that serves the five major universities and three Institutes in the Sydney-Newcastle region. The primary focus of this application is to create new facilities at the hubs of CVRCFGA that are integral to the analysis of molecular variation in a range of organisms. The study of molecular variation will enable researchers to understand better how organisms interact with each other, how they respond to environmental stress and aid in the identification of complez traits.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453724
Funder
Australian Research Council
Funding Amount
$532,824.00
Summary
Functional Genomics - Linking Genomics and Proteomics. This application is to enhance the capacity of the Ramaciotti Centre for Gene Function Analaysis (RCFGA) and its Nodes to support research in Functional Genomics by expanding its ability to link genomic analysis (including transcriptomics) with proteomic and cell biological analysis. It will provide access to novel methods for analysing interactions of proteins with other molecules by enabling the manufacture of protein arrays as well as DN ....Functional Genomics - Linking Genomics and Proteomics. This application is to enhance the capacity of the Ramaciotti Centre for Gene Function Analaysis (RCFGA) and its Nodes to support research in Functional Genomics by expanding its ability to link genomic analysis (including transcriptomics) with proteomic and cell biological analysis. It will provide access to novel methods for analysing interactions of proteins with other molecules by enabling the manufacture of protein arrays as well as DNA microarrays and to analyse the data obtained from them. This is a vital component to maintain gene function analysis at the cutting edge of current technology.Read moreRead less