Pathogenesis Of Vascular Shock And Platelet Dysfunction In Sepsis: The Role Of Calcium Desensitization, Statins And Cortisol.
Funder
National Health and Medical Research Council
Funding Amount
$89,778.00
Summary
Severe infections are characterised by a profound drop in blood pressure, which starve vital organs of oxygen and nutrients, this �septic shock� can lead to organ failure and death. We aim to identify dysfunction of the molecular signals in blood vessels, which leads to the failure of these vessels to maintain adequate blood pressure. Understanding the mechanisms regulating blood pressure during septic shock will enable us to develop therapies to support the circulation and reduce the significan ....Severe infections are characterised by a profound drop in blood pressure, which starve vital organs of oxygen and nutrients, this �septic shock� can lead to organ failure and death. We aim to identify dysfunction of the molecular signals in blood vessels, which leads to the failure of these vessels to maintain adequate blood pressure. Understanding the mechanisms regulating blood pressure during septic shock will enable us to develop therapies to support the circulation and reduce the significant death toll from life threatening sepsis.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
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
Failure-to-progress In Human Labour Results From A Profound Electrical Negativity Of The Uterine Cells: Targeting The Ion Channels Involved
Funder
National Health and Medical Research Council
Funding Amount
$564,541.00
Summary
The incidence of failure to progress in labour has increased in recent years, being linked to the rise in obesity. The result is a significant escalation in the rate of delivery by Caesarean Section (CS) which increases the risk of serious complications during subsequent pregnancies. We have identified dysfunctional systems associated with poor uterine contraction. We now aim to determine the mechanisms underlying these dysfunctional systems to lay the foundations for better therapeutics.
Role Of Pacemaker Cells In The Generation Of Slow Wave Activity In The Prostate Gland
Funder
National Health and Medical Research Council
Funding Amount
$231,500.00
Summary
The prostate gland commonly enlarges in ageing males resulting in a condition known as benign prostatic hyperplasia which is poorly understood. Because of the strategic position of the prostate, its enlargement physically compresses the segment of the urinary system passing through it causing inconvenient and distressing symptoms, such as difficulty and hesitancy in urination, which often require surgical or medical intervention. Indeed patients diagnosed with benign prostatic hyperplasia are of ....The prostate gland commonly enlarges in ageing males resulting in a condition known as benign prostatic hyperplasia which is poorly understood. Because of the strategic position of the prostate, its enlargement physically compresses the segment of the urinary system passing through it causing inconvenient and distressing symptoms, such as difficulty and hesitancy in urination, which often require surgical or medical intervention. Indeed patients diagnosed with benign prostatic hyperplasia are often treated with pharmacological agents that reduce the size of the prostate or relax the prostate and bladder, thus relieving some of the symptoms. However, the precise cellualr mechanisms by which many of these drugs mediate their effects have not been confirmed. Moreover, although previous studies of the prostate gland have clearly established many of the basic properties of the tissue, there is currently a lack of information regarding the prostate gland at a cellular level. We have recently identified a specialised group of 'interstitial cells' in the prostate gland, which resemble the well-described 'interstitial cells of Cajal' in the gut. In the gut, these cells perform a wide variety of functions including the initiation of contractile activity. Interstitial cells are also thought to play a role in diseases of the bowel. This project aims to investigate the role of the interstitial cells in the functioning of the prostate gland. In addition, the effects of age and hormones on the interstitial cells will be considered, which may lead to a better understanding of conditions such as benign prostatic hyperplasia. Finally, identifying nerve-released substances that may affect the activity of these cells may also help identify alternative targets for treatment of benign prostatic hyperplasia.Read moreRead less
Physiological And Pathological Effects Of Oxidation On Contractile Function In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$613,311.00
Summary
Reactive oxygen molecules generated within muscle fibres in normal exercise and in pathological conditions, greatly affect muscle function by altering the responsiveness of the contractile proteins. This study investigates how various oxidative stresses affect particular reactive sites on key proteins controlling muscle contraction. The findings should identify key molecular changes involved in normal activity and the role oxidation plays in chronic muscle weakness in particular conditions.
Investigation Of The Roles Of Calcium-dependent Proteases In Muscle Damage And Disease
Funder
National Health and Medical Research Council
Funding Amount
$360,160.00
Summary
Muscle strength is important to the health and well-being of everyone. Skeletal muscle weakening occurs as a result of certain disease states, aging and prolonged inactivity due to illness-injury-surgery. This can result in the loss of normal activity and mobility and an increased incidence of falls and accidents, which impact considerably on health care costs. There is a family of proteins called calpains that have been linked to a number of factors affecting muscle function, however it is not ....Muscle strength is important to the health and well-being of everyone. Skeletal muscle weakening occurs as a result of certain disease states, aging and prolonged inactivity due to illness-injury-surgery. This can result in the loss of normal activity and mobility and an increased incidence of falls and accidents, which impact considerably on health care costs. There is a family of proteins called calpains that have been linked to a number of factors affecting muscle function, however it is not known how they are involved. Calpains are proteases, ie. they destroy other proteins, and they are regulated by the concentration of calcium inside a cell. The calcium concentration increases dramatically inside a muscle cell when it contracts. Inside a muscle cell it is important that there is tight regulation of the calpains to avoid them being activated inappropriately during normal use and causing muscle damage. In certain disease states, such as types of muscular dystrophy, it is known that the calcium concentration within resting muscle fibres is increased compared with healthy muscle fibres. We propose that as a consequence of this, the calpains will be less regulated and will cause damage to the muscle, which contributes to the muscle weakness seen in these diseases. Whilst calpains have been implicated with symptoms associated with muscle dystrophies, the role they play is certainly unclear. The objectives of our research proposal are to understand what factors influence i) where the calpains are located and ii) when and how much they are activated, within muscle fibres. We will compare this in healthy muscle and muscle from mdx mice, an animal model of Duchenne muscular dystrophy.Read moreRead less
Role Of Nitric Oxide And Reactive Oxygen Species In Excitation-contraction Coupling In Skeletal Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$163,250.00
Summary
Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contr ....Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contribute towards the normal control of muscle contraction, while others contribute to its impairment. Reactive oxygen species (ROS), which includes nitric oxide (NO) and related molecules, are metabolic factors often referred to as cellular oxidants. They are thought to have an essential role in controlling normal muscle function. Paradoxically, they are also implicated in the impairment of muscle function associated with fatigue, disease and aging. How these molecules both control normal muscle activity and also contribute to impairment of such function remains unclear. Thus, the central aim of this project is to identify the mechanisms by which the cellular oxidants, NO and other ROS, both control normal E-C coupling in skeletal muscle fibres and how they contribute to muscle fatigue. Clearly, understanding how skeletal muscle normally contracts is essential in order to better understand how muscle function can become impaired with exercise, disease and age. The work from this study will provide insight into both normal muscle physiology and how muscles fatigue and ultimately provide new methodologies and drugs that may combat fatigue, disease and age related changes to muscle function.Read moreRead less