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
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.
Immunopathogenesis Of Human And Murine Herpes Simplex Infections
Funder
National Health and Medical Research Council
Funding Amount
$315,000.00
Summary
Herpes Simplex virus causes genital herpes, brain infections, eye infections and if passed by a mother to her infant during delivery can cause a highly damaging and sometimes lethal disease in the newborn. The virus has developed a number of strategies to overcome our immune system. The aim of this grant is to define some of these strategies in human tissue and in mice and in order to reverse them we are also defining the viral proteins which stimulate the critical immune cells . In addition we ....Herpes Simplex virus causes genital herpes, brain infections, eye infections and if passed by a mother to her infant during delivery can cause a highly damaging and sometimes lethal disease in the newborn. The virus has developed a number of strategies to overcome our immune system. The aim of this grant is to define some of these strategies in human tissue and in mice and in order to reverse them we are also defining the viral proteins which stimulate the critical immune cells . In addition we wish to understand the reasons why newborn babies have severe herpes disease compared to adults . What we learn from our experiments will assist us in developing a more effective vaccine against herpes and find new ways to treat this virus in the very young.Read moreRead less
Nanostructured Porous Silicon For Ophthalmic Implants
Funder
National Health and Medical Research Council
Funding Amount
$536,657.00
Summary
Blindness exerts major physical, emotional and economic constraints upon the sufferer. Our goal is to develop novel nanostructured porous silicon-based implants to improve outcomes for patients prone to recurrent episodes of inflammation in the eye, or with visual loss following ocular trauma or infection. Treatments are available, but are not always effective. Porous silicon is a non-toxic, non-inflammatory, biodegradable material that can be loaded with drugs or cells for transfer to the eye.
Pterygia, one of the most common ocular complaints in Australia and worldwide, are thought to originate from overexposure to UV light. We propose that UV-irradiation stimulate certain cells in the eye to produce cytokines, growth factors and enzymes which degrade scaffold proteins such as collagens. These enzymes may play a key role in the progressive and invasive nature of pterygia. Dissecting the mechanism(s) by which UV light induces these proteins will lead to new and more reliable therapies ....Pterygia, one of the most common ocular complaints in Australia and worldwide, are thought to originate from overexposure to UV light. We propose that UV-irradiation stimulate certain cells in the eye to produce cytokines, growth factors and enzymes which degrade scaffold proteins such as collagens. These enzymes may play a key role in the progressive and invasive nature of pterygia. Dissecting the mechanism(s) by which UV light induces these proteins will lead to new and more reliable therapies for the treatment of pterygia.Read moreRead less
Development Of A Novel Bioengineered Tissue Construct For Repairing The Eye.
Funder
National Health and Medical Research Council
Funding Amount
$335,817.00
Summary
Corneal diseases are often treated using donor tissue transplants. Nevertheless, donor tissue is unsuitable for treating the peripheral or limbal margin of the cornea. We have therefore developed a way to transplant sheets of limbal tissue (epithelium) grown in the laboratory from a patient's own cells, but this tissue lacks a foundation of connective tissue that we believe is essential for sustained healing. Thus, our aim is to develop a novel limbal transplant which contains both layers.
Dissecting The Pseudoexfoliation Syndrome With Complementary Genetic, Proteomic And Biophysical Strategies
Funder
National Health and Medical Research Council
Funding Amount
$490,352.00
Summary
Pseudoexfoliation syndrome (PEX) is an eye condition in which flaky material deposits in the eye, greatly increasing the risk of cataract and glaucoma which can lead to blindness. PEX is also associated with heart disease, strokes and aneurysms. Cataract surgery in PEX patients has a higher rate of complications. In this project we will determine the nature of PEX material and why it forms. This knowlege will facilitate better diagnosis and treatment of PEX preventing associated blindness.