Complement Regulation: Protection Against Xenograft Rejection, Ischaemia And Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Organ transplantation is an accepted solution to treat kidney, heart, lung and liver failure, and is being keenly sought for diabetes treatment. With refined surgical techniques and better controlled immunosuppression, the expected graft survival times are in years. However, the number of individuals who would benefit from transplants exceeds the supply of donor organs, and this number will increase as the benefits of having a transplanted organ increase. There is an active program to research t ....Organ transplantation is an accepted solution to treat kidney, heart, lung and liver failure, and is being keenly sought for diabetes treatment. With refined surgical techniques and better controlled immunosuppression, the expected graft survival times are in years. However, the number of individuals who would benefit from transplants exceeds the supply of donor organs, and this number will increase as the benefits of having a transplanted organ increase. There is an active program to research the possibility of using animal organs (xenografts). This project addresses one of the many issues arising from xenograft transplantation - the rapid activation of the body's complement system, which without treatment results in the very rapid rejection of the graft. In principle this problem can be solved by the development of transgenic donor animals that carry one or more human genes that produce a complement regulating protein, such as CD46 (MCP) or CD55 (DAF). In practice, however, to get successful longterm organ function still requires the selection of the optimal complement regulator or combination of regulators and an understanding of how they function. This research work analyses how CD46 and CD55 function to protect tissues from complement activation, and will result in selection of appropriate transgenes for xenografting. Another aspect of transplantation that is addressed in this proposal is the damage that a graft suffers when the blood supply is temporarily removed during organ harvest and the grafting procedure. This is similar to what occurs during a heart attack when a portion of heart muscle is starved of blood: as the blood flows again through the tissue there is a powerful reaction, again involving complement activation, which is known as reperfusion injury. We have found that perfusing a graft with a soluble form of the CD46 complement regulator provides protection against this damage. The research will measure and optimise this protection.Read moreRead less
Improved Ex-vivo Culture Of Keratinocytes For Clinical Applications
Funder
National Health and Medical Research Council
Funding Amount
$275,203.00
Summary
Skin cells grown for clinical applications currently require animal-derived cells and-or non-defined products for their expansion in the laboratory; these reagents can potentially infect patients who receive these therapies. This project will identify the essential components provided by these reagents and develop a fully synthetic and defined culture system. This improvement will provide safer, cost-effective grafts and cell-based therapies that will benefit patients suffering burns and wounds.
Characterisation Of MiRNAs That Regulate Vascular Leakage.
Funder
National Health and Medical Research Council
Funding Amount
$167,493.00
Summary
Vascular permeability or leak is a major problem in diseases such as cancer and in cardiovascular diseases . MicroRNAs (miRNAs) are small control genes that influence dveleopment and disease. We have identified a miRNA cluster in endothelial cells, the cells that line the blood vessels, that is important in the control of vascular leak. This project is focused on understanding the impact of these miRNAs in disease.
Role Of Epigenomic Changes In Conferring Hyperglycemic Memory
Funder
National Health and Medical Research Council
Funding Amount
$636,146.00
Summary
The major burden of type I diabetes remains its vascular complications including diabetes-accelerated athersclerosis. Despite improved glucose control, diabetic individuals develop complications as a result of prior poor glycemic control. Although the development and progression of these diabetic complications is strongly associated with mean levels of glucose, recent studies suggest that the deleterious effects of early exposure to high levels of glucose persist for years even after treatment h ....The major burden of type I diabetes remains its vascular complications including diabetes-accelerated athersclerosis. Despite improved glucose control, diabetic individuals develop complications as a result of prior poor glycemic control. Although the development and progression of these diabetic complications is strongly associated with mean levels of glucose, recent studies suggest that the deleterious effects of early exposure to high levels of glucose persist for years even after treatment has returned glucose levels towards normal.Read moreRead less
Early Events In Arteriolar Remodeling: Adaptation To Prolonged Vasoconstriction
Funder
National Health and Medical Research Council
Funding Amount
$415,750.00
Summary
Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes ....Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes within the vessel wall (for example thickening of the muscle layer). These adaptive processes may enable the forces of contraction to be maintained without continued energy expenditure and damage to the vessel per se. However, they can also contribute to long-term alterations in the control of blood pressure and perhaps contribute to states of hypertension as well as other common vascular diseases. For these studies we will use arterioles, isolated by microsurgical techniques, together with sophisticated computer and video-based approaches. These techniques allow arterioles to be studied under controlled conditions and relevant biochemical measurements performed. We will also use a cell model where cultured cells will be studied after defined periods of mechanical stimulation (for example stretch). Cells will be probed using a novel microscopic technique (atomic force microscopy) which enables the cell membrane to be studied with respect to changes in composition as well as physical characteristics (for example stiffness). The studies are relevant to our understanding of the normal adaptive processes occurring within blood vessels to control blood flow and pressure. The studies are also of direct relevance to our understanding of common vascular disease states including hypertension, complications of diabetes and chronic inflammatory disorders.Read moreRead less