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
Progenitor cells within the peritoneal cavity. Implantation of a foreign object into the peritoneal cavity of animals recruits undifferentiated cells of bone marrow origin that encapsulate the free-floating object, then differentiate into myofibroblasts. When large pieces of myofibroblast capsule tissue are subsequently grafted into autologous artery, bladder or vas deferens, they develop the structure and morphology of that organ. We hypothesise that multipotent progenitor cells sequestered t ....Progenitor cells within the peritoneal cavity. Implantation of a foreign object into the peritoneal cavity of animals recruits undifferentiated cells of bone marrow origin that encapsulate the free-floating object, then differentiate into myofibroblasts. When large pieces of myofibroblast capsule tissue are subsequently grafted into autologous artery, bladder or vas deferens, they develop the structure and morphology of that organ. We hypothesise that multipotent progenitor cells sequestered to the peritoneal cavity can be manipulated to differentiate along smooth muscle and other pathways. The proposed project aims to identify the origin of these cells and characterise the transcriptional program that regulates their differentiation.Read moreRead less
Transcriptional regulation of erythropoiesis. The major expected outcome from this proposal will be development of a pipeline for the study of how transcription factors work at a genome level. There will be national benefit in the areas of Frontier Technologies, and Promoting and Maintaining Good Health. There will be specific outcomes with respect to development of tests for human blood diseases, future design of drugs to target the aberrant activities of transcription factors in genetic and de ....Transcriptional regulation of erythropoiesis. The major expected outcome from this proposal will be development of a pipeline for the study of how transcription factors work at a genome level. There will be national benefit in the areas of Frontier Technologies, and Promoting and Maintaining Good Health. There will be specific outcomes with respect to development of tests for human blood diseases, future design of drugs to target the aberrant activities of transcription factors in genetic and degenerative diseases. Also, a strong bridge will be built upon the previous collaborations of the research teams in Brisbane and Pennsylvania, which will facilitate advanced teaching and training of Australian PhD and post-doctoral scientists.Read moreRead less
Muscle fibre excitability and calcium regulation in skeletal muscle of amphibians and mammals. The fundamental role of skeletal muscle is posture and movement. Essential for this is a specialised cell structure and a complex regulation of function. This project will define key aspects of muscle structure and functional regulation crucial to developing targets for improving function under stressed states such as fatigue, disease and age.
Memory and the temporal lobes. This project will use brain imaging techniques to investigate how humans perceive, combine and access stored knowledge about the world via different senses. This information will not only provide information on normal brain processes, but will also provide vital data on what happens to memory if certain regions of the brain become damaged.
Calcium regulation in the skeletal muscle triad and along the fibre. The fundamental role of skeletal muscle is posture and movement. Alterations in the normal way calcium regulates skeletal muscle function in fatigue, age and disease states causes loss of normal function. Preventing or controlling these changes is a key therapeutic aim. However, we currently lack full understanding of key mechanisms of calcium regulation in healthy skeletal muscle. This project will define key aspects of cal ....Calcium regulation in the skeletal muscle triad and along the fibre. The fundamental role of skeletal muscle is posture and movement. Alterations in the normal way calcium regulates skeletal muscle function in fatigue, age and disease states causes loss of normal function. Preventing or controlling these changes is a key therapeutic aim. However, we currently lack full understanding of key mechanisms of calcium regulation in healthy skeletal muscle. This project will define key aspects of calcium regulation that could be crucial to developing targets for improving function of skeletal muscle under stressed states.Read moreRead less
Calcium cycling and heat generation in skeletal muscle fibres. This project aims to uncover the mechanisms that enable mammalian skeletal muscle to play a major role in generating the heat required to maintain a constant body temperature. The ability to modulate body heat played a defining role in the evolution of species, their behaviour and global distribution. How heat production occurs in resting muscle is of fundamental importance and will be defined for the first time, providing new avenu ....Calcium cycling and heat generation in skeletal muscle fibres. This project aims to uncover the mechanisms that enable mammalian skeletal muscle to play a major role in generating the heat required to maintain a constant body temperature. The ability to modulate body heat played a defining role in the evolution of species, their behaviour and global distribution. How heat production occurs in resting muscle is of fundamental importance and will be defined for the first time, providing new avenues to manipulate metabolic rate and counter obesity.Read moreRead less
Prediction of outcome following whiplash injury: a multicentre international prospective study. The main aim of this study is to validate a set of biological and psychological prognostic indicators of outcome following whiplash injury that we have previously identified in a single centre prospective cohort. Validation will be in the context of a large multicentre international cohort. This will allow stakeholders involved in whiplash such as health care and insurance providers to predict with co ....Prediction of outcome following whiplash injury: a multicentre international prospective study. The main aim of this study is to validate a set of biological and psychological prognostic indicators of outcome following whiplash injury that we have previously identified in a single centre prospective cohort. Validation will be in the context of a large multicentre international cohort. This will allow stakeholders involved in whiplash such as health care and insurance providers to predict with confidence both those persons at risk of developing chronic symptoms as well as those with a good chance of full recovery. Furthermore the validation of the predictive capacity of these indicators will, for the first time, provide predictive markers that are amenable to specific early multiprofessional treatment interventions.Read moreRead less
High Resolution EM Tomography of Specialised Plasma Membrane Domains. This project will provide National benefits in two major areas. Firstly, these studies will greatly increase our understanding of the cellular structures which are crucial to the functioning of cells in the body. Understanding the structure of the components of animal cells in three dimensions will provide long-term benefits in the quest to understand how a cell works in health and what goes wrong in disease. Secondly, this pr ....High Resolution EM Tomography of Specialised Plasma Membrane Domains. This project will provide National benefits in two major areas. Firstly, these studies will greatly increase our understanding of the cellular structures which are crucial to the functioning of cells in the body. Understanding the structure of the components of animal cells in three dimensions will provide long-term benefits in the quest to understand how a cell works in health and what goes wrong in disease. Secondly, this project will allow us to develop the new method of electron microscope tomography and apply it to a crucial question in biology. This will be a vital technique for Australian investigators in the coming years and this project will allow scientists and students to be trained in these state-of-the-art techniques.Read moreRead less
The sulfate anion transporter gene, Sat1: physiology, regulation and developmental expression. Sulfate is an essential nutrient for cell growth and survival. The kidneys and liver help regulate sulfate levels in the body, by yet unknown mechanisms. Recently, we cloned a gene, Sat1, expressed in mouse liver and kidneys, which may be responsible for body sulfate maintenance. In this study, we will determine the physiological importance of Sat1 in cell growth/survival and in controlling body sulfa ....The sulfate anion transporter gene, Sat1: physiology, regulation and developmental expression. Sulfate is an essential nutrient for cell growth and survival. The kidneys and liver help regulate sulfate levels in the body, by yet unknown mechanisms. Recently, we cloned a gene, Sat1, expressed in mouse liver and kidneys, which may be responsible for body sulfate maintenance. In this study, we will determine the physiological importance of Sat1 in cell growth/survival and in controlling body sulfate levels. We will generate and characterise a Sat1 lacking mouse, study its expression during development and its effects on other genes. We will elucidate how body sulfate levels are maintained and its importance in cell growth/development.Read moreRead less