Macrophages: A Therapeutic Target In Peritoneal Dialysis-induced Fibrosis?
Funder
National Health and Medical Research Council
Funding Amount
$593,888.00
Summary
Fibrosis (scar tissue) in the abdominal cavity is a common side-effect of peritoneal dialysis (a treatment for kidney failure), and results in a life-threatening loss of dialysis function. The cells causing the fibrosis are uncertain. This project asks: Are inflammatory cells (macrophages) the source of peritoneal scar tissue? What regulates the fibrotic process? Answers may lead to strategies to prevent fibrosis induced by peritoneal dialysis, abdominal surgery or other causes.
Hyperplasia And Hypertrophy Of Airway Smooth Muscle In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$286,250.00
Summary
Asthma is common in Australia with significant morbidity and it is the 6th Australian National Health Priority. Examination of the airways in asthma shows increased thickness of the airway wall (remodeling), and inflammation. Most long-term asthma treatment is currently focussed on treating inflammation. Since the contribution of smooth muscle to remodeling and excessive airway narrowing is crucial and may be largely independent of airway inflammation, new treatments aimed at the smooth muscle a ....Asthma is common in Australia with significant morbidity and it is the 6th Australian National Health Priority. Examination of the airways in asthma shows increased thickness of the airway wall (remodeling), and inflammation. Most long-term asthma treatment is currently focussed on treating inflammation. Since the contribution of smooth muscle to remodeling and excessive airway narrowing is crucial and may be largely independent of airway inflammation, new treatments aimed at the smooth muscle are needed. Treatments must be based on knowledge of the factors which result in more smooth muscle - hypertrophy (enlargement of cells), hyperplasia (more cells) or deposition of proteins (extracellular matrix) between the muscle cells. Matrix is produced by airway myofibroblasts which are more numerous in asthma. These various contributing factors have different signals that can be targeted for treatment, however, information regarding their relative importance is scant. We propose to examine cases of mild and severe asthma using archived tissue blocks in a multi-centre collaborative study using stereological techniques not previously applied to the airway in man. This study is important because it will: 1. Yield new data regarding the degree to which hyperplasia, hypertrophy and increased extracellular matrix vary in the airways; 2. Provide direction for the development of treatments of increased smooth muscle in asthma; 3. Provide relevance and direction to animal and tissue studies of airway smooth muscle; 4. Yield new information on the number of myofibroblasts in mild and severe asthma; 5. Yield new information on the effects of corticosteroids on smooth muscle, extracellular matrix and myofibroblasts in severe, fatal asthma, and 6. Relate increased smooth muscle to increased extracellular matrix, numbers of myofibroblasts and other airway wall dimensions including those close to the airway surface. These may be used to monitor airway pathology in asthma.Read moreRead less
New Insights Into The Role Of Renal Endothelial Dysfunction In The Pathogenesis Of Glomerular Injury And Renal Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$577,722.00
Summary
This project will ascertain whether abnormal function of endothelial cells contribute to diabetic and non-diabetic kidney diseases, the leading cause of end-stage kidney disease. The outcome of this study will allow us to reevaluate the role of endothelial cells in kidney scarring, lead us to question our current approaches to the treatment and management of chronic kidney disease and eventually may be helpful for the design of novel therapies to treat chronic kidney diseases.
Scleroderma or systemic sclerosis is a debilitating disease that is characterised by fibrosis of multiple organs leading to organ failure and eventually death. There is currently no cure for the disease. We are beginning to find that a newly-discovered class of molecules, called microRNAs, regulate many disease states but its role in scleroderma has not been established. We aim in this study to identify disease-related changes in microRNAs which may subsequently be used as therapeutic targets.
Contribution Of Bone Marrow-derived Cells To Renal Fibrosis And Elucidation Of Cell Signalling Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$427,703.00
Summary
This study investigates the contribution of bone marrow-derived adult stem cells to the development of renal scarring, an important process proceeding to end-stage renal disease (ESRD). There is increasing evidence demonstrating that bone marrow (BM)-derived cells can transform into renal cells and participate in the repair of damaged renal blood vessels. Our recent study demonstrated BM-derived stem cells can also transform to renal myofibroblasts, the major cell type that contributes to the de ....This study investigates the contribution of bone marrow-derived adult stem cells to the development of renal scarring, an important process proceeding to end-stage renal disease (ESRD). There is increasing evidence demonstrating that bone marrow (BM)-derived cells can transform into renal cells and participate in the repair of damaged renal blood vessels. Our recent study demonstrated BM-derived stem cells can also transform to renal myofibroblasts, the major cell type that contributes to the development of kidney scarring. This suggests that BM-derived adult stem cells have dual roles: to repair or worsen the development of renal scarring. The present study investigates this adult stem cell's transformation and explores the potential measures to enhance the benefits and to block the harmful roles from these adult stem cells. The importance of BM-derived stem cells in the repair of damaged kidney will be determined and thus will provide preliminary insights into the future utilization of BM-derived stem cells in the treatment of chronic renal disease. Understanding the dual roles of BM-derived stem cells in experimental renal scarring, will lead us to question our current thinking and approaches to the treatment and management of renal fibrosis, and perhaps fibrosis in other organs. Evidence of two opposite roles which BM-derived adult stem cells play in the process of renal scarring may be helpful not only for the design of novel therapies to prevent or retard the progression of renal fibrosis, but also for manipulating adult stem cells for the treatment of renal disease.Read moreRead less
Atherosclerosis (hardening of the arteries) is the principal cause of heart attack, stroke and blockage of blood flow to the lower limbs. However, to date none of the biological or synthetic grafts used to bypass the narrowed regions of arteries is ideal. We have shown that lengths of silicone tubing placed into the peritoneal cavity of rats or rabbits becomes covered within 2 weeks by a capsule of granulation tissue (smooth-muscle-like cells and collagen) and mesothelial (endothelial-like) cell ....Atherosclerosis (hardening of the arteries) is the principal cause of heart attack, stroke and blockage of blood flow to the lower limbs. However, to date none of the biological or synthetic grafts used to bypass the narrowed regions of arteries is ideal. We have shown that lengths of silicone tubing placed into the peritoneal cavity of rats or rabbits becomes covered within 2 weeks by a capsule of granulation tissue (smooth-muscle-like cells and collagen) and mesothelial (endothelial-like) cells. The silicone tubing can be removed and the tissue turned inside out such that the endothelial-like cells now line the inside of the tube of living tissue, which resembles a blood vessel. These artificial blood vessels will be grown in the peritoneal cavity of rabbits, then grafted into the right carotid artery to replace a length of removed vessel. Their long-term (3,6,9 and 12 months) patency, reactivity, tensile strength and resistance to clot development will be assessed. Their susceptibility to atherosclerotic plaque development and blockage (as compared with natural carotid artery) will be examined in rabbits fed a cholesterol-enriched diet. Changes in gene expression as the artificial artery progressively develops will be examined, as will the potential to genetically manipulate the artificial artery to improve its functioning. Finally, attempts will be made to grow the vessels entirely in vitro. This novel vascular graft may open new options in the field of arterial reconstructive surgery for replacing or bypassing diseased vessels or as an access vessel for haemodialysis patients with end stage renal failure. This study will also provide new information on the biology of cells found in the peritoneal cavity and their alternative pathways for differentiation.Read moreRead less
Origin Of Cells In The 'artificial' Artery Grown In The Peritoneal Cavity
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Implantation of a foreign object (such as a sterile, flexible plastic tube) into the abdominal cavity of animals induces cells floating in the peritoneal fluid to form a capsule around the object. Over the next 2-3 weeks, the cells differentiate into fibroblasts then myofibroblasts. When this capsule of living tissue (in the appropriate moulded shape) is subsequently grafted into smooth muscle-rich organs such as artery, bladder, uterus or vas deferens to replace excised segments, it gains the s ....Implantation of a foreign object (such as a sterile, flexible plastic tube) into the abdominal cavity of animals induces cells floating in the peritoneal fluid to form a capsule around the object. Over the next 2-3 weeks, the cells differentiate into fibroblasts then myofibroblasts. When this capsule of living tissue (in the appropriate moulded shape) is subsequently grafted into smooth muscle-rich organs such as artery, bladder, uterus or vas deferens to replace excised segments, it gains the structure of the surrounding tissue and the myofibroblasts differentiate further into functional smooth muscle. This raises the question: what is the origin of the cells of the capsule? Our previous studies suggested that monocyte-macrophages stimulated to enter the abdominal cavity in response to the sterile foreign body might be the source of the cells. In the current study we will use transgenic (c-fms EGFP and c-fms Cre Z-AP) mice in which cells of monocyte-macrophage lineage are genetically labelled. These cells can be clearly distinguished from all other cells of the body, and analysis of capsules formed around foreign bodies will give us a definitive answer. We will using micro-array analysis, determine which growth factors-cytokines are important in regulating differentiation of the cells, and the role of physical factors (eg pulsatile stretching). Finally, we will determine whether these cells stimulated to enter the abdominal cavity are capable of differentiating along alternative pathways, such as cardiac muscle or liver cells. Knowledge gained will further the use of the abdominal cavity as a bioreactor in which to engineer tissues for organ replacement therapies. Identification of the mechanisms regulating the (trans)differentiation and biology of the cells may also assist in wound repair strategies to prevent pathologies caused by excessive myofibroblast accumulation and fibrosis.Read moreRead less