Engineered Antibody Fragments For The Diagnosis And Treatment Of Eye Disease
Funder
National Health and Medical Research Council
Funding Amount
$196,886.00
Summary
We plan to investigate the use of genetically-engineered antibody fragments in the diagnosis and treatment of clinically-important human eye diseases. The work will be carried out in experimental models, but the goal is to develop a new class of drugs that will be widely applicable in human inflammatory eye disease and eye infections. Antibodies are natural proteins, found in blood and body secretions, that protect humans from infections. However, they can be made in the laboratory and monoclona ....We plan to investigate the use of genetically-engineered antibody fragments in the diagnosis and treatment of clinically-important human eye diseases. The work will be carried out in experimental models, but the goal is to develop a new class of drugs that will be widely applicable in human inflammatory eye disease and eye infections. Antibodies are natural proteins, found in blood and body secretions, that protect humans from infections. However, they can be made in the laboratory and monoclonal antibodies in particular - those with a single defined specificity - have found widespread use in many medical applications. For the past 15 years, monoclonal antibodies have been used therapeutically, that is, they have been administered to humans to treat some diseases. Antibodies are big proteins that have multiple functions. Their very size and the multiplicity of their actions prevent their use in some therapeutic situations. In recent years, advances in genetic engineering and biotechnology have developed to the extent that small fragments of monoclonal antibodies can be produced in the laboratory with relative ease. Such fragments should have very substantial advantages over intact antibodies in the diagnosis and treatment of human eye disease. Engineered antibody fragments hold enormous potential for ophthalmic use, especially if they can be administered topically as eye-drops. In this project, we aim to determine whether antibody fragments can be used in the diagnosis and the treatment of four potentially blinding conditions: acute anterior uveitis and corneal graft rejection, which are inflammatory eye diseases, and herpetic keratitis and Acanthamoeba keratitis, which are eye infections.Read moreRead less
Brm And Brg-1 Protect From Ultraviolet Radiation-induced Skin And Ocular Damage
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
Ultraviolet radiation within sunlight is the most important environmental hazard to which Australians are exposed. It causes cancers of the skin and eye, in addition to other forms of skin and eye damage. However sunlight also has health benefits such as vitamin D production. To protect our health from the sun we need to understand how it causes damage and the meachanisms involved. We have discovered a new pathway that we plan to study, called Brm and Brg-1, that provides protection from UV.
Novel Ophthalmic Topical Formulation Targeting Molecular Pathogenesis Of Corneal Haze
Funder
National Health and Medical Research Council
Funding Amount
$296,090.00
Summary
Presently, no drugs are proven to cure corneal haze/scarring, major leading cause of global blindness. Haze is caused by eye trauma, infections or refractive laser surgeries. We aim to test a non toxic, novel ophthalmic topical formulation developed to act on molecular and cellular targets of haze formation. The successful completion of the study will determine formulation’s optimal dose, safety and efficacy for its future potential clinical use in reversing corneal scarring/haze without side ef ....Presently, no drugs are proven to cure corneal haze/scarring, major leading cause of global blindness. Haze is caused by eye trauma, infections or refractive laser surgeries. We aim to test a non toxic, novel ophthalmic topical formulation developed to act on molecular and cellular targets of haze formation. The successful completion of the study will determine formulation’s optimal dose, safety and efficacy for its future potential clinical use in reversing corneal scarring/haze without side effects.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
Mapping Of Genetic Traits In Experimental Models Using Databases
Funder
National Health and Medical Research Council
Funding Amount
$237,750.00
Summary
The project aims to detect genes that influence human traits. These traits could be a disease such as diabetes or they may be much less sinister, representing hearing range as an example. Many of these traits are difficult to detect because they are governed by many genes which may also interact with the environment to influence the trait. In order to detect genes in these traits we would like to simplify the complex interactions by eliminating the environment as a potential cause or concentrati ....The project aims to detect genes that influence human traits. These traits could be a disease such as diabetes or they may be much less sinister, representing hearing range as an example. Many of these traits are difficult to detect because they are governed by many genes which may also interact with the environment to influence the trait. In order to detect genes in these traits we would like to simplify the complex interactions by eliminating the environment as a potential cause or concentrating on a particular population where the incidence appears to be much greater. In human populations we have no control over the environmental exposures and we cannot restrict their movements. For this reason many genetic studies have been conducted in mice. Many strains of mice have been generated. Their environment can be strictly controlled, enabling a much better identification of disease genes. Since mice and humans share much of their genome they also share many of their genes and are often afflicted by the same diseases. Thus if we identify genes in mice we have a very good chance of identifying the equivalent human genes. The completion of sequencing for the human genome is being closely followed by the completion of the mouse genome, precisely because mice have been used for over 100 years for genetic studies. The data generated from these sequencing efforts and prior genetic studies is now accumulating in vast databases. These databases of DNA information can be used to map genes for traits. The idea is to determine the trait measurement for many mice in different strains and compare these trait levels to the DNA state (genotype) of markers in the genome of the strains. If these are associated it indicates that the marker is situated close to a gene influencing the trait. This narrows the search considerably. Without this strategy we would have the daunting task of identifiying trait genes from many thousands of potential candidates.Read moreRead less
Studies Of Antigen Presenting Cells In The Anterior Segment Of The Eye And Their Role In Immune-mediated Ocular Disease
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
Dendritic cells (DC) are considered the 'sentinels' of the immune system because they are capable of trapping antigenic material derived from invading organisms such as bacteria and viruses in peripheral tissues-organs (skin, gut, respiratory tract etc) and then transporting these antigens to the lymphoid organs where they 'alert' the immune system to potential 'dangers' and elicit appropriate T cell responses. If the antigens are novel this mechanism forms the basis of primary cell-mediated imm ....Dendritic cells (DC) are considered the 'sentinels' of the immune system because they are capable of trapping antigenic material derived from invading organisms such as bacteria and viruses in peripheral tissues-organs (skin, gut, respiratory tract etc) and then transporting these antigens to the lymphoid organs where they 'alert' the immune system to potential 'dangers' and elicit appropriate T cell responses. If the antigens are novel this mechanism forms the basis of primary cell-mediated immune responses. Previously 'educated' T cells may upon contact with antigens in the periphery (when presented by other antigen presenting cells [APCs], such as macrophages) become activated. This forms the basis for secondary immune responses. Immune and inflammatory responses in the eye are held in check to avoid permanent damage to the delicate tissues and maintain visual function. The mechanisms which regulate immunological responses in the eye are only now becoming clear. Studies in the Chief Investigators laboratory over the last 7 years have been aimed at unravelling the life cycle and function of APCs in the eye. The present study has three specific aims: 1) Determining whether DC in the eye once they have taken up antigens migrate to the spleen or local lymph nodes? 2) The second aim of this project is to use an animal model of uveitis and transfer fluorescent labelled donor T cells to study the events in the living eye which lead to autoimmune uveoretinitis. In particular we wish to identify the cells that present antigen to infiltrating lymphocytes. 3) Patients often develop posterior uveitis (an autoimmune condition) after a cold or bacterial infection. We aim to mimic conditions of acute inflammation in the eye to see whether this may secondarily predispose the eye to attack by autoreactive lymphocytes.Read moreRead less
THE ROLE OF MONOCYTIC LINEAGE CELLS IN MODELS OF CORNEAL DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$311,567.00
Summary
Vision relies on sharp, focused undistorted images passing through the cornea, the clear 'window' at the front of the eye. Corneal disease causes over 5 million cases of blindness worldwide. In patients who damage the delicate covering of the cornea, due to trauma or contact lens wear, there is an increased risk of infection that may lead to blindness. This project will study the ways in which immune cells in the cornea detect invasion by potential pathogens.
Interaction Of Genetic And Environmental Risk Factors In Eye Disease
Funder
National Health and Medical Research Council
Funding Amount
$456,641.00
Summary
I aim to discover the genetic risk factors associated with a debilitating infection of the front of the eye caused by an amoeba, and associated with water use and contact lenses; and dry eye disease, a condition affecting over 20% of the elderly, and has significant affects on quality of life and functioning. The relationship of genetic and environmental factors will lead to identification of at risk populations, novel treatment paradigms and more sophisticated diagnostic techniques.
Toxoplasma Gondii Infection Of Human Retinal Pigment Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$460,668.00
Summary
Ocular toxoplasmosis is a vision-threatening parasitic eye infection that is common in Australia and worldwide. No treatment cures the disease. This work will characterize cellular and molecular events occuring in the eye during an infection, which is an important first step toward the development of more effective treatments for patients with the condition.