Many products are applied to the skin to prevent skin cancer or to treat skin diseases. This project seeks to better understand how we can make such products more affective, safer and appropriate for conditions such as psoriasis. One major component of the grant is concerned with the evaluation of nanotechnology products applied to the skin.
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
This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on hu ....This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on human mast cells grown in culture. We will characterise the chemical nature of this receptor and verify that it is functionally important in mast cell activation. Because mast cells reside in almost all body tissues and are also important mediators of host responses to infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. Another key cell in allergic and parasitic diseases is the eosinophil. We have found that two other S100 proteins are expressed in eosinophils from the blood of normal individuals and that the genes that encode these proteins are regulated by mediators that regulate eosinophil migration and survival at allergic sites. However although the numbers these cells are high in lung biopsies from patients with asthma, we find that these proteins are generally not expressed. Because one of the S100 proteins, S100A9, was recently found to be important in the ability of other blood cells to migrate to signals that recruit them into tissues, we will examine whether this protein regulates the ability of eosinophils to migrate. Results from this project will provide new knowledge concerning mechanisms of allergy and may lead to the design of novel strategies to regulate the process. Results may have broader ramifications applicable to other inflammatory and infectious diseases.Read moreRead less
Epidermal Growth Control In Psoriasis And Normal Skin
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
Our skin protects us from damage, dehydration, infection and harmful UV radiation. At the same time, we expect it to remain healthy, smooth and looking good. How the skin, and more particularly its upper layer, the epidermis, adapts to all these requirements is a complex problem yet to be fully understood. This question forms the basis of our project proposal. The epidermis is a continuously self-renewing tissue, in which cells have an average life of 30 days before they are invisibly shed to th ....Our skin protects us from damage, dehydration, infection and harmful UV radiation. At the same time, we expect it to remain healthy, smooth and looking good. How the skin, and more particularly its upper layer, the epidermis, adapts to all these requirements is a complex problem yet to be fully understood. This question forms the basis of our project proposal. The epidermis is a continuously self-renewing tissue, in which cells have an average life of 30 days before they are invisibly shed to the outside. In normal states and when responding to injury or disease, this cell turnover speed can be finely tuned, for example accelerated in the case of a healing wound. In contrast, if damaged by the sun, epidermal cells undergo a form of cell suicide (apoptosis) to prevent tumours forming from cells with damaged genes. This changing turnover speed is controlled by a series of growth factors, or cytokines. Insulin-like growth factor-I (IGF-I) is a unique cytokine that can control both cell turnover rate, and cell death. We aim to uncover the complex biochemical interactions that allow the epidermal IGF-I system to achieve this seemingly contradictory task. This study is important because when the epidermis loses the ability to finely tune its turnover speed, ulcers, sun damage, the common skin disorder psoriasis, or worse still, skin tumours, arise. This project explores ways of manipulating the IGF-I system to prevent this, and builds on some technology developed by the research group that has already proven effective in the control of psoriasis. The project also promises to discover undiscovered growth regulators that could be used in new gene therapies for skin overgrowth diseases.Read moreRead less
Cell Cycle Regulation By The Epidermal Growth Factor Receptor
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The rate of growth and death of normal cells is regulated through signals transmitted from the cell surface to the nucleus. In many human cancers the normal regulatory mechanisms are subverted, leading to uncontrolled growth of the cells. We aim to characterize the signals that are initiated by binding of the Epidermal Growth Factor (EGF) to its receptor and to understand how these signals influence the ability of the cell to divide and to survive. We will identify the pathways that contribute t ....The rate of growth and death of normal cells is regulated through signals transmitted from the cell surface to the nucleus. In many human cancers the normal regulatory mechanisms are subverted, leading to uncontrolled growth of the cells. We aim to characterize the signals that are initiated by binding of the Epidermal Growth Factor (EGF) to its receptor and to understand how these signals influence the ability of the cell to divide and to survive. We will identify the pathways that contribute to uncontrolled growth in tumor cells. This knowledge is necessary for the design of new therapies targetted to the molecular lesions which stimulate solid tumors.Read moreRead less
LPS-regulated SNAREs And Control Of Cytokine Secretion In Macrophages.
Funder
National Health and Medical Research Council
Funding Amount
$470,750.00
Summary
TNF(tumour necrosis factor alpha) is a potent proinflammatory cytokine secreted by immune activated macrophages. TNF has essential roles in host defense, tumour killing and energy metabolism. Excessive secretion of TNF in acute and chronic inflammatory conditions, such as septic shock, Crohn s disease, rheumatoid arthritis and in cancer has many severe, even fatal, consequences. Improved anti-TNF therapeutics are needed for clinical management in all of these conditions. Our studies are focused ....TNF(tumour necrosis factor alpha) is a potent proinflammatory cytokine secreted by immune activated macrophages. TNF has essential roles in host defense, tumour killing and energy metabolism. Excessive secretion of TNF in acute and chronic inflammatory conditions, such as septic shock, Crohn s disease, rheumatoid arthritis and in cancer has many severe, even fatal, consequences. Improved anti-TNF therapeutics are needed for clinical management in all of these conditions. Our studies are focused on investigating how macrophages synthesize and secrete TNF, with the ultimate goal of characterizing the molecules and vesicles in the TNF secretory pathway. Our recent findings show the expression of SNARE proteins, part of the vesicle docking and fusion machinery, is regulated in concert with cytokine secretion and other trafficking changes in activated macrophages. We identified the proteins Syntaxin4, Munc-18c and SNAP-23 as the specific t-SNARE complex that regulates TNF delivery to the cell surface. In the proposed studies we will investigate how SNAREs are regulated during macrophage activation by studying their gene expression and protein modifications. We have developed a single-cell assay to measure TNF trafficking in macrophages; this allows the identification of molecules with roles in TNF secretion and it will be used in a series of experiments to identify the specific v-SNARE proteins that partner the t-SNARE for TNF delivery. Finally we will use live cell imaging to investigate how and where TNF is delivered to the macrophage cell surface and membrane fractionation to examine a role for membrane microdomains in organizing SNARE-mediated TNF secretion. Manipulation of SNAREs, using data generated by these studies, holds potential for the development of new anti-TNF therapies.Read moreRead less
Evaluation Of Specificity, Mechanism Of Action And Therapeutic Use Of Peptides That Disrupt T-cell Antigen Receptor
Funder
National Health and Medical Research Council
Funding Amount
$166,885.00
Summary
Molecular disorganisation of receptor assembly renders the receptor incompetent and the cell unable to perform its normal function. In autoimmune diseases where the target is self the ability to stop autoreactive T cells is a therapy. Synthetic compounds known as peptides have been developed in our laboratory with the ability to disrupt cell function and we are at the forefront of such research. We hypothesise that if you prevent the receptor from assembling properly then it will not function. T ....Molecular disorganisation of receptor assembly renders the receptor incompetent and the cell unable to perform its normal function. In autoimmune diseases where the target is self the ability to stop autoreactive T cells is a therapy. Synthetic compounds known as peptides have been developed in our laboratory with the ability to disrupt cell function and we are at the forefront of such research. We hypothesise that if you prevent the receptor from assembling properly then it will not function. The end result is the potential to develop novel drugs with new means to treat inflammation in a number of autoimmune disorders including diabetes, rheumatoid arthritis, multiple sclerosis and psoriasis. Application of this concept is not restricted to immunology or the disruption of the T-cell antigen receptor but has wider therapeutic application to other multicomponent receptors relevant in the field of oncology, endocrinology, and allergy. By design one can produce peptides that will specifically inhibit specific cellular functions based on structure-function relationships. Further research into this area will then allow design of new non-peptide chemical entities based on the original peptide sequence and structure with easier pharmacological handling properties and efficacy. This project aims to define necessary features of the peptide and test it in humans.Read moreRead less