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
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
Age Related Changes In The Optics Of Adult Human Eyes
Funder
National Health and Medical Research Council
Funding Amount
$199,437.00
Summary
Vision is limited by both optical and retinal-neural factors. Our understanding of the optical structure of the human eye is limited, partcularly for the refractive index gradient of the lens, let alone how these change with age. This understanding is needed if we are to accurately predict or assess the long-term effects of refractive surgical procedures or ophthalmic prostheses on vision. In this project, we aim to substantially improve our understanding of the optical properties of the eye by ....Vision is limited by both optical and retinal-neural factors. Our understanding of the optical structure of the human eye is limited, partcularly for the refractive index gradient of the lens, let alone how these change with age. This understanding is needed if we are to accurately predict or assess the long-term effects of refractive surgical procedures or ophthalmic prostheses on vision. In this project, we aim to substantially improve our understanding of the optical properties of the eye by 1) developing methods for measuring these quantities and then applying the methods to investigate how these properties vary with age and focussing, and 2) determine the optical contribution to reduction in visual performance with increasing age. Our research will be used to determine norms for growth and aging patterns in the normal human eye, particularly the lens. It will yield significant outcomes through 1. determination of the long-term success of custom refractive surgery aimed at improving vision by eliminating the ocular aberrations, and 2. indicating the potential improvement in ocular performance provided by artificial intraocular lenses or any other type of correction.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