Linking mutant zebrafish phenotypes with their underlying genetic lesions. Zebrafish mutants have been generated with many interesting abnormalities, but to understand these abnormalities, the defective genes must be identified by positional cloning. We seek to identify the defective genes underpinning four mutants. Mutant #562 develops a normal nervous system which then undergoes rapid degeneration. The mutant flotte lotte has abnormal gut development. Two mutants with defective early blood for ....Linking mutant zebrafish phenotypes with their underlying genetic lesions. Zebrafish mutants have been generated with many interesting abnormalities, but to understand these abnormalities, the defective genes must be identified by positional cloning. We seek to identify the defective genes underpinning four mutants. Mutant #562 develops a normal nervous system which then undergoes rapid degeneration. The mutant flotte lotte has abnormal gut development. Two mutants with defective early blood formation will be studied. We will establish techniques for several steps that will be useful for all zebrafish mapping projects. We expect the genetic characterization of these mutants to provide new insights into nerve cell survival, gut development, and blood formation.Read moreRead less
The Production of Respiratory Cell Lineages from Human Embryonic Stem Cells: Towards a Cell Replacement Therapy for the Treatment of Respiratory Specific Deficits. Embryonic stem (ES) cells are a primitive embryonic cell type that can be maintained and grown in vitro. Mouse ES cells can be instructed to develop into a wide range of specific adult cell types. Research into human ES cells has more recently commenced and has already resulted in the controlled production of specific nerve cells by o ....The Production of Respiratory Cell Lineages from Human Embryonic Stem Cells: Towards a Cell Replacement Therapy for the Treatment of Respiratory Specific Deficits. Embryonic stem (ES) cells are a primitive embryonic cell type that can be maintained and grown in vitro. Mouse ES cells can be instructed to develop into a wide range of specific adult cell types. Research into human ES cells has more recently commenced and has already resulted in the controlled production of specific nerve cells by our group. The following project aims to create respiratory lineages from both mouse and human ES cells. Such an undertaking thus aims to provide a basis for the treatment of respiratory specific diseases such as cystic fibrosis and emphysema.Read moreRead less
Developing technologies that support the genetic modification of rats. Rats and the mouse play critical roles in medical research. Until recently, the targeted genetic modification of a mammal was limited to the mouse. This was due to a technology that was unique to the mouse: embryonic stem (ES) cells. These cells have not been isolated from any other species. The recent development of animal cloning allows for an alternate strategy for targeting genes. We propose to develop cloning strate ....Developing technologies that support the genetic modification of rats. Rats and the mouse play critical roles in medical research. Until recently, the targeted genetic modification of a mammal was limited to the mouse. This was due to a technology that was unique to the mouse: embryonic stem (ES) cells. These cells have not been isolated from any other species. The recent development of animal cloning allows for an alternate strategy for targeting genes. We propose to develop cloning strategies in the rat that supports the genetic modification of this animal. The development of this technology will bring considerable benefits to the areas of physiological research and drug design.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 Molecular Basis of Copper Metabolism in Sheep. The unusual copper metabolism of sheep represents a significant agricultural problem. They are very susceptible to copper deficiency, but readily accumulate copper to toxic levels in the liver leading to fatal liver failure. We propose to elucidate the reason for the copper accumulation phenotype of sheep. We are focussing on WND, a copper transporter responsible for copper excretion into bile. We discovered a novel form of sheep WND designated ....The Molecular Basis of Copper Metabolism in Sheep. The unusual copper metabolism of sheep represents a significant agricultural problem. They are very susceptible to copper deficiency, but readily accumulate copper to toxic levels in the liver leading to fatal liver failure. We propose to elucidate the reason for the copper accumulation phenotype of sheep. We are focussing on WND, a copper transporter responsible for copper excretion into bile. We discovered a novel form of sheep WND designated WNDb to distinguish it from the normal form, WNDa. The experiments outlined are designed to understand the function of both proteins in the sheep and their role in copper sequestration.Read moreRead less
Rapid functional analysis of genes involved in skeletal development. Abnormalities of the skeleton are of enormous clinical significance in terms of both number of individuals affected and the cost of treatment. Data derived from this project will underpin targeted research on the mechanisms of inherited and common diseases of cartilage and bone, yielding novel diagnostic and therapeutic targets. In addition, the improved knowledge of cartilage and bone cell development will inform new approache ....Rapid functional analysis of genes involved in skeletal development. Abnormalities of the skeleton are of enormous clinical significance in terms of both number of individuals affected and the cost of treatment. Data derived from this project will underpin targeted research on the mechanisms of inherited and common diseases of cartilage and bone, yielding novel diagnostic and therapeutic targets. In addition, the improved knowledge of cartilage and bone cell development will inform new approaches for developing stem cell therapies and the production of novel biomaterials for the repair of bones and joints. The outcomes of this study will therefore benefit the full spectrum of society from infants to the aged.Read moreRead less
Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behav ....Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behaviour of therapeutic stem cells introduced into the body.Read moreRead less
Gene targeting in the rat germ cell. The rat plays a central role in both medical research and the drug development process. Unfortunately key technologies supporting the genetic modification of the rat are currently unavailable. The development of such technology would dramatically improve the utility of the rat in many areas of medical research as well as for the pharmaceutical industry. This project proposes to develop methods to perform gene targeting experiments in the germ cells of the ....Gene targeting in the rat germ cell. The rat plays a central role in both medical research and the drug development process. Unfortunately key technologies supporting the genetic modification of the rat are currently unavailable. The development of such technology would dramatically improve the utility of the rat in many areas of medical research as well as for the pharmaceutical industry. This project proposes to develop methods to perform gene targeting experiments in the germ cells of the male rat. Successful manipulation of these cells will represent a major breakthrough towards the ultimate goal of manipulating the rat genome.Read moreRead less