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
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