Aberrant Mesenchymal-epithelial Transition: A Pathogenic Mechanism In Tissue Maintenance And Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$522,299.00
Summary
The causative genetic factors associated with aberrant changes of cellular properties are identified by analysing the profile and the control mechanism of gene expression. Specifically,this project will reveal how the transition of different patterns of tissue organization may be manifested in birth defects and malignant diseases.
This work will analyse how cells, the building blocks of tissues, are organized together to form functioning organs. It focuses on the adhesion molecules that allow cells to recognize one another, which cooperate with the internal skeleton of cells to link them together. We aim to understand how these cellular systems work normally and how they are targeted to disrupt tissue integrity in diseases like cancer and inflammation.
TGFbeta Isoforms Differentially Regulate Fibrosis And Inflammation In Diabetic Nephropathy Via KLF Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$540,639.00
Summary
Progressive scarring and inflammation in the kidney represent the final common injury pathway for diseases that lead to kidney failure, including diabetic nephropathy. This project explores the interplay between the molecular processes that are triggered by high glucose levels in patients with diabetic nephropathy, some of which are deleterious and some potentially 'protective'. By understanding these mechanisms we will be able to prevent and more effectively treat kidney disease in diabetes.
MicroRNAs are small molecules that modulate the expression of most genes and so affect nearly every biological process and pathology although, they were only discovered in humans less than 10 years ago. The bottleneck in discovering the functions of miRNAs is in identifying their molecular targets, the majority of which remain unknown. We aim to comprehensively identify direct target genes of epithelial-specific microRNAs and to confirm a number of them by gene target validation approaches.
Epithelial-mesenchymal Transformation In Diabetic Nephropathy: Roles Of Oxidative Stress And KLF Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$557,523.00
Summary
Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction ....Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction is possibly the greatest predictor of subsequent cardiovascular events (including heart attack, heart failure and stroke) a thorough understanding of the mechanism of progressive kidney failure in patients with diabetes is required so that effective therapeutic strategies may be developed. Preliminary data leading to the development of this proposal, has shown that normal kidney tubule cells 'transform' into fibroblastic-like cells, in a process known as epithelial-mesenchymal transformation (EMT), under the metabolic disturbances inherent in diabetes mellitus. These fibroblast-like cells are likely to be responsible for the progressive scarring in the kidney that is characteristic of irreversible renal failure. We have documented that a specific factor, transforming growth factor beta (TGFB1) is increased in kidney cells in the presence of diabetes mellitus, and our preliminary data suggests the action of TGB1 is regulated by the KLF-family of transcription factors. This project aims to determine whether metabolic conditions such as exposure to high glucose and oxidative stress induced by diabetes mellitus modifies the KLF factors within cells that then alter susceptibility to TGFB1 induced EMT. The specific pathways involved in EMT will be dissected using both cell culture models and animal models of diabetes mellitus. These pathways will be selectively interrupted to assess reversibility of the EMT process.Read moreRead less
Role Of The MiR-200 Target Quaking In Alternative Splicing During EMT And Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$443,160.00
Summary
The spread of cancer to other organs involves cancer cells changing to a more aggressive state and is a major cause of cancer related death. MicroRNAs are a class of genes that control whether cancer cells become more aggressive by regulating other genes. In this project we will examine the function of a new microRNA target which controls the cancer cell aggression. The outcome will be a better understanding of how cancers spread and the identification of new therapeutic targets.
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
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause which is unresponsive to current therapy. This study builds on recent work by this group highlighting the importance of a cell signalling molecule called STAT3 in the development of this disease. In particular, two cell types that utilise STAT3 signalling, epithelial cells and B cells, will be examined to see if blocking their STAT3 responses could be a novel therapeutic approach.
REVERSING EPITHELIAL TO MESENCHYMAL TRANSITION BY TARGETED EPIGENETIC EDITING IN BREAST CANCER
Funder
National Health and Medical Research Council
Funding Amount
$1,352,322.00
Summary
Cancer cell spread around the body involves changes in the cells which allow them to migrate into blood vessels, travel and then invade other organs, a process called epithelial mesenchymal transition (EMT). EMT also makes cells less sensitive to our best treatments. EMT involves switching on genes that activate these changes and switching off genes that silence them. We will develop therapy that will reverse this process, both reducing cancer spread and making cancer treatment more effective.
Targeting MicroRNA-driven Mesenchymal To Epithelial Transition To Suppress Prostate Cancer Metastasis
Funder
National Health and Medical Research Council
Funding Amount
$741,831.00
Summary
Prostate cancer kills ~3,000 men per year in Australia. The development of metastasis is the major cause of prostate cancer-associated death and has limited treatment options. In this study, we will characterise the role of a group of molecules, termed microRNAs, in prostate cancer metastasis. We will also test whether targeting microRNAs using novel drugs termed antagomiRs is an effective strategy to inhibit metastasis and thereby improve prostate cancer mortality.