Identification Of Critical Factors For The Establishment And Maintenance Of The Epidermal Barrier
Funder
National Health and Medical Research Council
Funding Amount
$671,424.00
Summary
The human skin plays a crucial role in the body’s defence against our hostile environment. The outer most layer of the skin, the epidermis is essential for formation and repair of the skin barrier. We have identified a family of genes that are pivotal for skin development and function. Disruption of these genes has disastrous consequences, including loss of barrier function and the development of skin cancers. This project examines how these diseases occur.
Regulatory Interactions Between YAP And Beta-catenin In Normal Epidermal Homeostasis And In Skin Cancer
Funder
National Health and Medical Research Council
Funding Amount
$396,157.00
Summary
Australia has the highest skin cancer incidence in the world. We found that oncoprotein YAP activates stem cell proliferation in the skin through activation of the Wnt pathway, and we have evidence that YAP is hyperactivated in human skin cancer. We will map out the molecular nature of the interaction between YAP and the Wnt pathway in normal epidermal homeostasis and in skin cancer. This study will provide novel insights for development of therapeutic avenues for human skin cancer and other reg ....Australia has the highest skin cancer incidence in the world. We found that oncoprotein YAP activates stem cell proliferation in the skin through activation of the Wnt pathway, and we have evidence that YAP is hyperactivated in human skin cancer. We will map out the molecular nature of the interaction between YAP and the Wnt pathway in normal epidermal homeostasis and in skin cancer. This study will provide novel insights for development of therapeutic avenues for human skin cancer and other regenerative dermatological disorders.Read moreRead less
Microenvironmental Regulation Of The Tissue Regenerative Capacity Of Keratinocyte Stem Cells And Their Progeny.
Funder
National Health and Medical Research Council
Funding Amount
$391,762.00
Summary
The protective outer layers of the skin known as the epidermis belongs to a group of tissues in the body that are turning over at a rapid rate. The majority ofepidermal cells have a lifespan of just 2-3 weeks, and are shed as mature cells from the skin's surface. These cells are replaced by continuous cell regeneration which is dependent on growth factors and adhesive molecules (and other signals). It has recently come to light that the connective tissue of the skin i.e. the dermis, which lies d ....The protective outer layers of the skin known as the epidermis belongs to a group of tissues in the body that are turning over at a rapid rate. The majority ofepidermal cells have a lifespan of just 2-3 weeks, and are shed as mature cells from the skin's surface. These cells are replaced by continuous cell regeneration which is dependent on growth factors and adhesive molecules (and other signals). It has recently come to light that the connective tissue of the skin i.e. the dermis, which lies directly below the epidermal cells has a critical role in providing some of these factors required for their growth and maturation. Indeed, it is becoming increasingly clear that the epidermal and dermal cells co-operate to regulate epidermal proliferation and maturation. Recent work from our laboratory has shown that a newly recognised adhesive protein laminin-10 may be produced as the result of such co-operation and that it stimulates the growth of both normal and tumour epidermal cells. We have also recently identified an interesting subset of dermal cells that may have a role in promoting the growth of the epidermal cells. Thus, the aims of the proposed stuides are to investigate the role of laminin-10 and this specific dermal cell subset in epidermal proliferation and maturation. These studies may also provide an insight into the role of these factors in skin cancers.Read moreRead less
Identification And Characterization Of A Novel Tumor Suppressor
Funder
National Health and Medical Research Council
Funding Amount
$591,997.00
Summary
Australia has the highest rate of skin cancer in the world, with over 380,000 people diagnosed every year. Of these, over 370,000 have non-melanoma skin cancers including squamous cell carcinoma and basal cell carcinoma. Our laboratory has identified a gene in mice that protects animals from squamous cell cancer. The studies proposed in this grant examine the mechanisms underpinning this protective role and may have important implications for the prevention of skin cancers in humans.
Developmental Potential Of Murine Keratinocyte Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The stem cells of the epidermis or outer lining of the skin are an important group of cells with a role in normal cell replenishment, in wound healing and in skin disorders such as psoriasis and cancer. These primitive cells remain in the skin during the lifetime of an individual and are responsible for the production of mature, functional cells that form a protective barrier against the environment and pathogens. We have recently developed a strategy for the isolation of stem cells of the skin ....The stem cells of the epidermis or outer lining of the skin are an important group of cells with a role in normal cell replenishment, in wound healing and in skin disorders such as psoriasis and cancer. These primitive cells remain in the skin during the lifetime of an individual and are responsible for the production of mature, functional cells that form a protective barrier against the environment and pathogens. We have recently developed a strategy for the isolation of stem cells of the skin which places us in a unique position to further study these cells and determine possible therapeutic approaches for the future. The aims of this project encompass testing the potency of skin stem cells (i) to reform complex structures such as a mature epidermis, hair follicles and sebaceous glands; and (ii) to give rise to cells from other tissues such as muscle and liver. A final aim of this project is to dissect the complexity of the stem cell compartment further to gain insights into how normal skin growth is regulated.Read moreRead less
MPM Non-invasive Imaging Of Biological Interactions Following Drug Delivery With Micro-nanoprojection Patches.
Funder
National Health and Medical Research Council
Funding Amount
$403,612.00
Summary
The overarching aim of my research is to develop and evaluate effective, practical and reproducible physical methods for delivering genes and drugs to specific immunologically-sensitive cells in the skin to ultimately treat and vaccinate against human diseases. I recently patented a method using arrays of nano-scale projections on a patch to accurately, efficiently and safely deliver biomolecules not just to specific skin cells, but also to organelles within them. Conceptually, the delivery devi ....The overarching aim of my research is to develop and evaluate effective, practical and reproducible physical methods for delivering genes and drugs to specific immunologically-sensitive cells in the skin to ultimately treat and vaccinate against human diseases. I recently patented a method using arrays of nano-scale projections on a patch to accurately, efficiently and safely deliver biomolecules not just to specific skin cells, but also to organelles within them. Conceptually, the delivery device is a set of microscopic nanoneedles coated with drug substance and applied to the skin as a small patch. The device is practical, needle-free and pain-free. The aim of this current project is to use the micro-nanoprojection array patches-configured to uniquely deliver biomolecules to cells within given strata-to find: 1) what delivery sites of antigen-expression plasmid- toll like receptor (TLR) agonist lead to strong humoral immune responses in the intact animal. 2) whether delivery of different TLR agonists have different effects on the maturation and migration of the different professional antigen presenting cells (APCs) in the skin, as visualised locally by Multi-Photon Microscopy (MPM). 3) whether differences in APC maturation and migration are associated with different systemic antibody responses. We will identify optimal delivery sites of drugs-vaccines to the skin (layer, cells targeted, duration of delivery) with MPM for desired systemic immune responses. This will have important contributions towards improving immunotherapeutics of major diseases via skin targeting with micro-nanoprojection array patch technologies (and other methods).Read moreRead less
A Novel Tumour Suppressor Function Of E2F7 In Squamous Cell Carcinoma Formation
Funder
National Health and Medical Research Council
Funding Amount
$524,124.00
Summary
squamous cell carcinomas of the skin are the second most common skin cancer. In this proposal we present data showing that a new gene, E2F7, may play an important role in the development of squamous cell carcinoma. If true, these studies will identify a new therapeutic target that could be exploited in developing novel anticancer therapies.
The Biology Of Events Following Reactivation Of Herpes Simplex Virus.
Funder
National Health and Medical Research Council
Funding Amount
$388,522.00
Summary
Herpes simplex virus causes genital herpes, severe disease in neonates, cold sores and occasionally fatal encephalitis. It lies doemant within nerve cells near the spine and reactivates intermittently, travelling down nerves to cause the characteristic ulcers in the skin, including the genitals. This grant has two major components. In the first we aim to continue studies which are defining the way in which Herpes simplex viruses assemble within nerve cells. These processes have always been the s ....Herpes simplex virus causes genital herpes, severe disease in neonates, cold sores and occasionally fatal encephalitis. It lies doemant within nerve cells near the spine and reactivates intermittently, travelling down nerves to cause the characteristic ulcers in the skin, including the genitals. This grant has two major components. In the first we aim to continue studies which are defining the way in which Herpes simplex viruses assemble within nerve cells. These processes have always been the subject of much debate and have never been properly studied in the nerve cells in which the virus lives. Furthermore the way in which herpes simplex virus enters the processes of nerve cells and moves to the cell body will be studied by similar techniques. Such studies may contribute to the development of herpes simplex virus as a vector for gene therapy for treatment of diseases of the nervous system. The second part of the grant will examine the immune processes that occur in the skin during the early stages of a recurrent herpes simplex lesion. In particular there is a linkage between nerves and the major cells in the skin which present viral antigen to defensive T-cells. This link may provide a route for direct access of herpes simplex virus to these cells. In previous work the viral protein targets in infected skin cells for killer T-cells which infiltrate the skin have been defined. In this grant we also aim to find the stretches of amino acids which are specifically targetted by these cells.Read moreRead less