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
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
The Role Of Crim-1 In Lens Development And Eye Disease.
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
We have recently isolated a novel gene (Crim1) and shown it to be strongly expressed during eye development. Its protein structure indicates that it may act to regulate the activities of two growth factor families, the TGF superfamily and the insulin-IGFs. These growth factors effect the behaviour of many cell types that influence events in normal and pathological development. For example in the eye lens, TGF 1 can induce cataractous changes in epithelial cells and early differentiating fibres; ....We have recently isolated a novel gene (Crim1) and shown it to be strongly expressed during eye development. Its protein structure indicates that it may act to regulate the activities of two growth factor families, the TGF superfamily and the insulin-IGFs. These growth factors effect the behaviour of many cell types that influence events in normal and pathological development. For example in the eye lens, TGF 1 can induce cataractous changes in epithelial cells and early differentiating fibres; however, TGF signalling appears to be required for events in late stages of fibre cell maturation. Cataract is the leading cause of blindness and arises when lens cell architecture is disrupted and-or proteins aggregate abnormally. In humans, following ocular trauma, eye surgery, or in association with other diseases, cataracts can develop. These cataracts feature the development of subcapsular fibrotic plaques which obscure vision. We have shown that lenses cultured in the presence of TGF can mimic production of these plaques suggesting that these cataracts result from inappropriate activation of TGF . TGF is expressed in the lens and is abundant in the ocular media that bathes the lens. Thus, it appears that complex regulation of TGF bioavailability is required; epithelial cells and young fibre cells need to be protected from its cataractogenic effects, whereas older fibres require TGF signalling for maturation and-or survival. The expression pattern of Crim1 in the lens is consistent with it having a key role in inhibiting TGF in the lens. Thus, we hypothesise that Crim1 plays important roles in the lens, possibly via the modulation of members of the TGF superfamily and insulin-IGFs. We predict that Crim1 acts to maintain the lens epithelial phenotype and facilitate events in early fibre differentiation. If so, this may have implications for devising molecular strategies for preventing or slowing diseases, such as the various forms of human cataract.Read moreRead less