Regulation Of Lens Cell Behaviour By RTK Antagonists, Sef And Sprouty.
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Cataract, the loss of transparency of the eye lens, is a major cause of world blindness. 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 localised differentiation into fibres. As disruption to this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation will provide insights into the mecha ....Cataract, the loss of transparency of the eye lens, is a major cause of world blindness. 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 localised differentiation into fibres. As disruption to this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation will provide insights into the mechanisms involved in cataract formation. Following cataract surgery, for example, many patients develop aftercataract which results from residual lens cells. These residual cells, unlike those tightly regulated in the normal lens, divide and differentiate to form a secondary cataract. The main aim of this study is to understand what molecules regulate the proliferation and differentiation of lens cells. Growth factors are key regulators of cell behaviour and our studies provide evidence that FGF growth factors play pivotal roles in the lens by influencing cell proliferation and differentiation. We have recently identified inhibitors of FGF in the lens, called Sprouty and Sef; molecules shown in other systems to effectively block FGF intracellular signalling pathways. To understand how Sef and Sprouty regulate lens cell proliferation and fibre differentiation, we plan to examine what regulates their expression, and more importantly their role in FGF-induced cell signalling in normal lens biology. To do this, we will use a well established explant culture system to monitor the effectiveness of these endogenous inhibitors on growth factor-induced lens cell proliferation and differentiation, as well as use transgenic mice technology to determine the role they play in situ. By understanding the molecular and cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.Read moreRead less
Genetic And Molecular Basis Of Congenital Cataracts
Funder
National Health and Medical Research Council
Funding Amount
$454,510.00
Summary
Cataracts are caused when the lens of the eye (which focuses light), loses transparency. They typically occur in older individuals, but can also occur in children, even as early as from birth. They usually result in severe vision impairment which can result in complete blindness. The only treatment is invasive surgery where the outcomes are poor, particulary in very young children. This research aims to discover the genes that cause cataract in children and to investigate how cataracts form. We ....Cataracts are caused when the lens of the eye (which focuses light), loses transparency. They typically occur in older individuals, but can also occur in children, even as early as from birth. They usually result in severe vision impairment which can result in complete blindness. The only treatment is invasive surgery where the outcomes are poor, particulary in very young children. This research aims to discover the genes that cause cataract in children and to investigate how cataracts form. We are working with several large Australian families that have severe childhood cataracts in order to identify the specific genes that cause their disease. This is achieved through an investigation of the entire genome of these families which allows us to precisely pinpoint any genetic changes. We can then look for these changes in the genes in other childhood cataract patients as well as in adults with cataracts. This information will increase our understanding of how the lens of the eye works and how cataracts can form. One gene that can cause cataracts has already been identified, this is the Nance-Horan Syndrome gene. We will investigate the role of this gene in the lens of the eye. This gene also causes other severe disabilities including mental retardation. The exact function of this gene is unknown but by determining how it works we will be able to better understand cataract formation and mental retardation, with the ultimate aim of developing better diagnosis and timely treatment for these disorders.Read moreRead less
The Roles Of Beta-catenin, APC And The Wnt/beta-catenin Pathway In Lens Development And Cataract
Funder
National Health and Medical Research Council
Funding Amount
$456,764.00
Summary
Cataract is a leading cause of blindness. Many risk factors have been identified but the basic cellular and molecular mechanisms that cause cataract are not well understood. Investigation of these mechanisms is essential to identify potential targets for future therapies to arrest or prevent cataract formation. The lens is composed of epithelial and fibre cells. Much of our research has focussed on identifying genes and cell signalling pathways that regulate formation of fibre cells from the epi ....Cataract is a leading cause of blindness. Many risk factors have been identified but the basic cellular and molecular mechanisms that cause cataract are not well understood. Investigation of these mechanisms is essential to identify potential targets for future therapies to arrest or prevent cataract formation. The lens is composed of epithelial and fibre cells. Much of our research has focussed on identifying genes and cell signalling pathways that regulate formation of fibre cells from the epithelial cells. However, considerably less is known about factors that regulate formation of the epithelium itself. As the epithelial cells are affected in some types of cataract it is vitally important to understand the mechanisms that control formation and maintenance of these cells. Our previous studies have identified a growth factor family (TGF-beta) that causes epithelial cataracts. Importantly, our recent studies have identified another growth factor signalling pathway (Wnt-beta-catenin) as being essential for the formation and maintenance of the lens epithelium. We hypothesise that this pathway is disrupted dring cataract formation. This project uses state of the art tools and techniques to investigate the role of two central molecular components of this Wnt pathway (APC and beta-catenin) in the developing lens. By genetically manipulating the activity of these proteins in the mouse lens we will investigate the roles these molecules and the Wnt signalling pathway play in lens development and whether inappropriate activity results in abnormal development or cataract. We will also be able to investigate whether modulating this pathway affects the formation of epithelial cataracts by TGFbeta. The results will provide detailed information on how these molecules regulate lens structure and function and have the potential to identify targets for preventing or ameliorating cataracts.Read moreRead less