Identification And Characterisation Of Novel Genes For Congenital Cataract
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Cataracts are the leading cause of blindness worldwide. The term describes a clouding of the lens which may lead to visual impairment. Congenital cataracts (present at birth) are less common than age-related cataract but the lifelong impact on vision can be severe, with a third of patients remaining legally blind. Late complications such as aphakic glaucoma may be blinding. We have shown that congenital cataracts are often inherited and have performed a population-based study in South-Eastern Au ....Cataracts are the leading cause of blindness worldwide. The term describes a clouding of the lens which may lead to visual impairment. Congenital cataracts (present at birth) are less common than age-related cataract but the lifelong impact on vision can be severe, with a third of patients remaining legally blind. Late complications such as aphakic glaucoma may be blinding. We have shown that congenital cataracts are often inherited and have performed a population-based study in South-Eastern Australia over the past 5 years to determine the causative genes. A large number of families have been involved in the study and solid progress has been made in identifying mutations in cataract genes and understanding what effect these may have on the patient's prognosis. We have recently identified a new gene in a large Australian family with a syndrome of cataract, mental retardation and teeth problems. This syndrome, known as Nance-Horan syndrome was originally described in Australia 30 years ago and we have worked with the original family to find the exact gene responsible. We already know that this gene causes the same syndrome in other families and in this project we will examine whether it can cause cataract without the other features or mental retardation without cataract. We will perform a series of experiments to learn what this gene does and how it causes the disease. We have also selected 3 other very interesting families with congenital cataracts for further study as we either know already or strongly suspect that they will enable us to identify further new genes for cataract, and in one case mental retardation. Our work in other diseases indicates that understanding the genes in severe young onset cases can give valuable clues to the causes of age-related forms and may in the future enable new ways to prevent and treat the commonest cause of worldwide blindness.Read moreRead less
Roles For MAPK-ERK1-2, -catenin-TCF And Smad3 Mediated Signalling Pathways In TGF -induced Cataract
Funder
National Health and Medical Research Council
Funding Amount
$339,071.00
Summary
Posterior capsular opacification (PCO) is a common and costly complication of cataract surgery that is caused by aberrant growth of lens cells. The TGF growth factor family causes PCO. TGF activates three signalling pathways in the lens, MAPK-ERK1-2, -catenin-TCF and Smad3; however currently we do not know which one induces PCO. This project will identify the pathway(s) that prevent TGF from causing cataracts. This is critical for the development of pharmaceuticals to prevent PCO.
Expression And Role Of Integrins During Lens Development And Cataractogenesis
Funder
National Health and Medical Research Council
Funding Amount
$336,760.00
Summary
Cataract is the leading cause of blindness in the world. Numerous risk factors for cataract have been identified, but little is known about the cellular and molecular mechanisms that underlie this debilitating disease. Development of adequate treatments or, eventually, a cure for cataract will require a better understanding of the basic molecular mechanisms that regulate normal lens development and the formation of cataract. The research outlined in this application builds upon our previous rese ....Cataract is the leading cause of blindness in the world. Numerous risk factors for cataract have been identified, but little is known about the cellular and molecular mechanisms that underlie this debilitating disease. Development of adequate treatments or, eventually, a cure for cataract will require a better understanding of the basic molecular mechanisms that regulate normal lens development and the formation of cataract. The research outlined in this application builds upon our previous research, which has identified molecules (growth factors) that are involved in either the regulation of normal lens development and growth (FGF and TGF-beta) or the induction of cataractous changes in the lens epithelium (TGF-beta). The studies are directed at identifying members of an important family of cell adhesion molecules, the integrins, in the lens and examining the role that these molecules play in controlling lens structure and function. These cell surface glycoproteins function in adhesion of cells to each other and to extracellular matrix, and transmit signals in response to changes in the extracellular environment. Such responses include cell proliferation, migration and differentiation. In this regard they often act in concert with growth factor receptors (eg. FGF and TGF-beta). After defining where and when integrins are expressed in the developing lens we will investigate their function in mediating various lens cell responses by using genetic manipulations to alter the expression of integrins or their intracellular signaling mediators in lenses of transgenic mice. In addition, a lens explant culture system will be used to investigate the roles integrins play during lens development and during formation of anterior subcapsular cataract by TGF-beta. These studies will provide important insights into the molecular mechanisms that control cellular events in normal and abnormal lens development.Read moreRead less
Translational Clinical Research In Major Eye Diseases (TCR-Eye)
Funder
National Health and Medical Research Council
Funding Amount
$2,552,355.00
Summary
The four eye diseases that cause the majority of vision loss in Australia, age-related macular degeneration, diabetic retinopathy, cataract and glaucoma, impose a significant socio-economic burden, costing our nation -$lo billion a year. This CCRE will fund a world leading, broad-based, clinical and translational research program in Melbourne and Sydney to tackle these eye diseases. The new knowledge and innovative clinical strategies developed in this CCRE will impact on clinical ophthalmology ....The four eye diseases that cause the majority of vision loss in Australia, age-related macular degeneration, diabetic retinopathy, cataract and glaucoma, impose a significant socio-economic burden, costing our nation -$lo billion a year. This CCRE will fund a world leading, broad-based, clinical and translational research program in Melbourne and Sydney to tackle these eye diseases. The new knowledge and innovative clinical strategies developed in this CCRE will impact on clinical ophthalmology and the practice of other medical disciplines.Read moreRead less
Analysis Of FGF Receptor Signalling Involved In Lens Cell Proliferation And Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$343,028.00
Summary
Cataract, the loss of transparency of the eye lens, is the leading cause of blindness in the world. An eventual cure for cataract depends on a better understanding of the basic molecular processes in the normal and cataractous lens. Our research has focussed on identifying the molecules that control the formation and maintenance of the lens. Growth factors are important regulators of cell behaviour and our studies have provided compelling evidence that members of the FGF growth factor family pla ....Cataract, the loss of transparency of the eye lens, is the leading cause of blindness in the world. An eventual cure for cataract depends on a better understanding of the basic molecular processes in the normal and cataractous lens. Our research has focussed on identifying the molecules that control the formation and maintenance of the lens. Growth factors are important regulators of cell behaviour and our studies have provided compelling evidence that members of the FGF growth factor family play pivotal roles in lens developmental biology by influencing lens cell proliferation and differentiation. An important finding from our laboratory is that FGF induces lens epithelial cell proliferation and differentiation at different concentrations. The FGFs elicit intracellular responses upon binding to and activating cell surface FGF receptors (FGFRs). The FGFRs are membrane bound tyrosine kinases which upon activation, activate specific signalling pathways leading to a specific cellular response. To understand how FGFs mediate and regulate different responses in lens cells, namely cell proliferation and fibre differentiation, we plan to examine the role of FGFRs in normal lens development using genetically altered FGFRs that will be expressed specifically in lenses of transgenic mice. While it is known that four different FGF receptor genes are expressed by the normal developing lens, it is unknown what role each of these play in the process of lens cell proliferation and differentiation. In addition, as we can reproduce a specific FGF-induced lens cellular response in vitro, we will use our lens explant culture system to dissect the signalling pathway(s) downstream from specific receptor activation and correlate this with a specific cellular response. By identifying the molecules and mechanisms that control the cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.Read moreRead less
Dissecting The Pseudoexfoliation Syndrome With Complementary Genetic, Proteomic And Biophysical Strategies
Funder
National Health and Medical Research Council
Funding Amount
$490,352.00
Summary
Pseudoexfoliation syndrome (PEX) is an eye condition in which flaky material deposits in the eye, greatly increasing the risk of cataract and glaucoma which can lead to blindness. PEX is also associated with heart disease, strokes and aneurysms. Cataract surgery in PEX patients has a higher rate of complications. In this project we will determine the nature of PEX material and why it forms. This knowlege will facilitate better diagnosis and treatment of PEX preventing associated blindness.
Growth-factor Induced Signalling Pathways Involved In The Regulation Of Lens Cell Behaviour
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Cataract, the loss of transparency of the eye lens, is a major cause of blindness in the world. A cure for cataract depends on a better understanding of the molecular processes in the normal and cataractous lens. Lens growth is regulated by controlled proliferation of epithelial cells and their precise localised differentiation into fibres. As disruption of this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation may provide insights ....Cataract, the loss of transparency of the eye lens, is a major cause of blindness in the world. A cure for cataract depends on a better understanding of the molecular processes in the normal and cataractous lens. Lens growth is regulated by controlled proliferation of epithelial cells and their precise localised differentiation into fibres. As disruption of this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation may provide insights into the mechanisms involved in cataract formation. Following cataract surgery, for example, a number of patients develop aftercataract which results from the response of lens cells remaining after surgery. These residual cells, unlike those tightly regulated in the normal lens, begin to divide and differentiate in an attempt to form a new lens. The main aim of this study is to understand what regulates the proliferation and differentiation of lens cells. Growth factors are key regulators of cell behaviour and our studies provide evidence that members of the FGF, PDGF and IGF growth factor families play pivotal roles in the lens by influencing cell proliferation and differentiation. Growth factors stimulate cellular processes by activating specific cell surface receptors. Once activated, these receptors switch on specific intracellular signalling pathways leading to a specific cellular response. To understand how different growth factors mediate and regulate lens cell proliferation and fibre differentiation, we plan to examine the role of FGF-, PDGF- and IGF-induced signalling in normal lens biology. To do this, we will use a well established lens explant culture system to dissect the signalling pathway(s) downstream of specific receptor activation and correlate this with a specific cellular response. By understanding the cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.Read moreRead less