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
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.
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
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
Inductive Interactions Between Lens And Optic Cup Specify Cell Fates
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
Normal eye development depends on interactions between embryonic eye tissues. In the front part of the eye inductive interactions between lens and optic vesicle are important for the formation and growth of lens, ciliary body and iris. Our recent studies indicate that a family of developmentally important growth factors, the Wnts, plays key roles in this process. Our proposed studies will examine, for the first time, the role of Wnts in lens, ciliary body and iris development. Specific experimen ....Normal eye development depends on interactions between embryonic eye tissues. In the front part of the eye inductive interactions between lens and optic vesicle are important for the formation and growth of lens, ciliary body and iris. Our recent studies indicate that a family of developmentally important growth factors, the Wnts, plays key roles in this process. Our proposed studies will examine, for the first time, the role of Wnts in lens, ciliary body and iris development. Specific experimental outcomes will show if Wnts are important in promoting the formation and maintenance of the front part of the lens, the lens epithelium. The outcomes will also give us information on the molecules that mediate the effects of Wnts on lens cells and if regulatory factors from the lip of the optic cup-ciliary body can influence the pathways by which Wnts can influence the lens cells. In addition we will learn if lens-derived Wnts have a role in the formation of ciliary body and iris. Identifying factors that regulate the formation of eye tissues is fundamental to understanding the molecular basis of eye disease. For example, cataract is the most common cause of blindness in the world. Cataract surgery is the most common surgical procedure and is placing an ever-increasing burden on health care budgets. Cataracts that most commonly require surgery usually involve abnormal growth and behaviour of lens cells such as occurs in posterior subcapsular cataract and posterior capsular opacification (also known as aftercataract because it occurs subsequently to cataract surgery). Identifying molecules and mechanisms that are involved in normal formation and growth of lens cells is fundamental to understanding these diseases. In addition, as it is well known that the lens is required for the normal formation of the front part of the eye, including the ciliary body and iris, results from this study may also shed light on some developmental abnormalities such as small eye.Read moreRead less
The Role Of The Posterior Cingulate Cortex In Verbal Associative Learning
Funder
National Health and Medical Research Council
Funding Amount
$146,500.00
Summary
Functional magnetic resonance imaging (fMRI) is a technique which utilises differences between oxygenated and deoxygenated blood to identify regions which are active when the brain is performing a task. This enables us to determine the regions of the brain which are involved in performing different functions. The brain regions supporting memory and learning functions include the hippocampus, the posterior cingulate cortex (PCC), and the frontal lobes. Research has already established the importa ....Functional magnetic resonance imaging (fMRI) is a technique which utilises differences between oxygenated and deoxygenated blood to identify regions which are active when the brain is performing a task. This enables us to determine the regions of the brain which are involved in performing different functions. The brain regions supporting memory and learning functions include the hippocampus, the posterior cingulate cortex (PCC), and the frontal lobes. Research has already established the importance of the hippocampus in memory and learning. However, the exact role of the PCC and the interaction between the PCC and other memory regions remains unclear. This study will use fMRI to investigate the role of the PCC in memory and learning. Specifically, we will compare the activity associated with performance of a difficult memory task and an easier memory task in healthy subjects. The study will then be repeated in patients sustaining damage to the hippocampus. This part of the study will allow us to see how the PCC adapts to disease in the memory system. The results of this study will further clarify the role of the PCC in memory and learning. In addition, this work may be of great importance in the treatment and rehabilitation of patients with memory disorders.Read moreRead less
The Role Of Integrins In The Regulation Of Scleral Remodelling During Pathological Myopia Development
Funder
National Health and Medical Research Council
Funding Amount
$234,750.00
Summary
Myopia (short-sightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. Most myopia is easily corrected with spectacles or contact lenses. However a small, but significant, group of individuals (in Australia, 1-2% of people) have high degrees of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina which is the light s ....Myopia (short-sightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. Most myopia is easily corrected with spectacles or contact lenses. However a small, but significant, group of individuals (in Australia, 1-2% of people) have high degrees of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina which is the light sensitive part of the eye. Any damage that occurs to the retina in these eyes is, at present, untreatable and irreversible and can result in blindness. In fact, myopia is the 2nd leading cause of blindness amongst adults of working age. In order for the eye to grow so large its white, outer coat (the sclera) must expand without allowing any leaks of the delicate structures and fluids inside. Although the sclera gets very thin as it expands, it has been shown that this process of expansion is not just due to stretching. Before any stretching can occur the biochemical structure of the sclera must change and this is a complex process, driven by the scleral cells and involving the synthesis of structural components and activity of enzymes which breakdown scleral structure. The aim of this project is to investigate the role of specific scleral proteins (integrins) in high myopia. Integrins reside on the surface of the scleral cells and communicate information about the changes going on in the surrounding sclera. We predict these proteins are important in keeping the cell informed of the local biochemical and biomechanical changes in the sclera and in driving the cell to rapidly adapt to these changes. The project will provide a greater understanding of the process of scleral thinning in high myopia and allow us to test the potential of integrins as therapeutic targets in the sclera, thereby giving us the opportunity of preventing blindness in a number of highly myopic individuals.Read moreRead less
Therapeutic Regulation Of Matrix Metabolism To Stabilise The Biomechanical Properties Of The Sclera In High Myopia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Myopia (short-sightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. Most myopia is easily correctable with spectacles or contact lenses. However a small, but significant, group of individuals have excessively long eyes and extreme amounts of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina which is the light s ....Myopia (short-sightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. Most myopia is easily correctable with spectacles or contact lenses. However a small, but significant, group of individuals have excessively long eyes and extreme amounts of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina which is the light sensitive part of the eye. Any damage that occurs to the retina in these eyes is, at present, untreatable and irreversible and can result in blindness. In fact, myopia is the 2nd leading cause of blindness amongst adults of working age. In order for the eye to grow so large its white, outer coat (the sclera) must expand without allowing any leaks of the delicate structures and fluids inside. Although the sclera gets very thin as it expands, it has been shown that this process of expansion is not just due to stretching. Before any stretching can occur the biochemical structure of the sclera must change. A complex process, involving the synthesis of structural components and the activity of enzymes that breakdown these structural components, is at work in the sclera of eyes that are rapidly enlarging. The aim of this project is to intervene in the biochemical processes that have already been shown to be involved in excessive eye enlargement. We will use both therapeutic agents and innovative gene therapy techniques to reverse the biochemical changes that occur in the sclera of rapidly enlarging eyes. We predict that these therapies will result in a sclera that is more resistant to being stretched and an eye that has less pathology. The results from this study will provide us with potential therapeutic strategies for the treatment of eyes that are enlarging excessively, thereby giving us the opportunity of preventing blindness in a number of highly myopic individuals.Read moreRead less