Role Of Protease Activated Receptors Type 2 (PAR2) During Inflammation Of Airways And Intestine
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in PAR2 is found in various diseases which are paralle ....Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in PAR2 is found in various diseases which are paralleled by a strong inflammation. Thus, PAR2 is likely to play a central role in intestinal diseases such as acute infectious diarrhea and chronic inflammatory bowel disease. PAR2 may also participate in the severe diarrhea frequently observed in patients with intestinal tumors. Similarly, inflammatory mediators released during airway infections are likely to act on PAR2, causing inappropriate secretion and a running nose. Most importantly, PAR2 are found in large excess in the airways of asthma patients. Since nothing is known about the impact of these receptors on fluid and electrolyte transport in the airways it appears timely and highly relevant to study the function of PAR2 in the airway epithelium. We will assess PAR2 mediated responses in human nasal biopsies. A more detailed analysis of the intracellular processes will be done in mouse trachea. We will further study the function of PAR2 in the intestinal epithelium. Activation of the ion transport via PAR2 will be examined in the mouse distal colon and in human rectal biopsies. We will utilize techniques such as Ussing chamber and patch clamp recordings to analyze the transport processes. The results should gain new inside into the role of PAR2 during inflammatory diseases of the airways and the intestine such as asthma and chronic inflammatory bowel diseases.Read moreRead less
Regulation Of The Activity And The Surface Expression Of Sodium Channels
Funder
National Health and Medical Research Council
Funding Amount
$466,980.00
Summary
The regulation of transport of salt into and out of the body is essential for the maintenance of blood pressure, and for the maintenance of the correct amount of fluid in the respiratory passages and gut. A critical component of the mechanism by which the body transports salt are sodium channels. Overactivity of these channels leads to increased blood pressure and clogging of the gut and the bronchi due to thick and sticky secretions. Reduced activity leads to abnormally low blood pressure, as w ....The regulation of transport of salt into and out of the body is essential for the maintenance of blood pressure, and for the maintenance of the correct amount of fluid in the respiratory passages and gut. A critical component of the mechanism by which the body transports salt are sodium channels. Overactivity of these channels leads to increased blood pressure and clogging of the gut and the bronchi due to thick and sticky secretions. Reduced activity leads to abnormally low blood pressure, as well as to accumulation of fluid in the lungs such as occurs in influenza and in altitude sickness. The present project will examine the mechanisms by which sodium channels are regulated. It will particularly focus on the mechanisms by which sodium channels are switched off when the salt content of cells is too high.Read moreRead less
Regulation Of Epithelial Sodium Channels By Caveolin
Funder
National Health and Medical Research Council
Funding Amount
$408,391.00
Summary
Abnormal sodium absorption in the kidney, gut and lung is implicated in hypertension, cystic fibrosis and pulmonary oedema. Epithelial Na+ channels are a key component of the mechanism by which these organs absorb sodium. The project will investigate the mechanisms by which the activity of these channels is controlled and is intended to discover new approaches to treating abnormal sodium absorption.
Interactions Between Systems That Control Sodium Channels In Renal Epithelia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The transport of sodium ions by the kidney, gut and lungs not only regulates blood pressure, it also regulates the amount of fluid in the gut and in the lungs. One of the most important proteins that underlie the transport of sodium in these tissues is the so-called epithelial sodium channel. The activity of these epithelial sodium channels is regulated by a wide variety of systems. Some of these regulatory systems act in response to changes in the body's requirements for sodium transport. Other ....The transport of sodium ions by the kidney, gut and lungs not only regulates blood pressure, it also regulates the amount of fluid in the gut and in the lungs. One of the most important proteins that underlie the transport of sodium in these tissues is the so-called epithelial sodium channel. The activity of these epithelial sodium channels is regulated by a wide variety of systems. Some of these regulatory systems act in response to changes in the body's requirements for sodium transport. Others act in response to changes in capacity of cells in which the sodium channels are found to continue transporting sodium. In this project we will study the mechanisms that regulate the activity of the epithelial sodium channels, and in particular, how these mechanisms interact so as to maintain a level of sodium channel activity that is appropriate to both the needs of the organism and to the needs of the sodium transporting cells. The outcomes of this project will be improved understanding of the function of the kidney, gut and lungs in both health and disease. It may also lead to novel drug targets for treatment of major diseases in which the activity of sodium channels is abnormal. These disease include hypertension, cystic fibrosis, pulmonary oedema and influenza.Read moreRead less
Regulation Of The Epithelial Sodium Channel By Cytosolic Chloride And Pro-inflammatory Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
The regulation of sodium transport by the epithelial sodium channel is essential for the maintenance of blood pressure and the correct amount of fluid in the respiratory tract and gut. Hyperactivity of the sodium channels leads to increased blood pressure and clogging of the gut and bronchi due to dehydration of the surface fluid. Reductions in the activity of the sodium channels lead to abnormally low blood pressure and the accumulation of fluid in the lungs such as occurs in influenza, high al ....The regulation of sodium transport by the epithelial sodium channel is essential for the maintenance of blood pressure and the correct amount of fluid in the respiratory tract and gut. Hyperactivity of the sodium channels leads to increased blood pressure and clogging of the gut and bronchi due to dehydration of the surface fluid. Reductions in the activity of the sodium channels lead to abnormally low blood pressure and the accumulation of fluid in the lungs such as occurs in influenza, high altitude pulmonary oedema and in cardiogenic pulmonary oedema. The present project will examine the mechanisms by which sodium channels are regulated. It will focus on the mechanisms by which cytosolic chloride and inflammatory mediators regulate the activity of the channels.Read moreRead less
A Randomised Controlled Trial Of A Fluid Containing 140mmol/L Of Sodium Compared To A Fluid Containing 77mmol/L Of Sodium For Maintenance Intravenous Fluid Therapy In Hospitalised Children.
Funder
National Health and Medical Research Council
Funding Amount
$183,959.00
Summary
Intravenous fluid therapy is one of the most common and important treatments for children in hospital. In spite of this we know very little about what fluid should be used and there is now good evidence that children are experiencing adverse outcomes because of fluid treatment. The aim of this trial is to determine which intravenous fluid is best in children. It will be the largest and most relevant intravenous fluid trial performed in children. The results will have an immediate impact on treat ....Intravenous fluid therapy is one of the most common and important treatments for children in hospital. In spite of this we know very little about what fluid should be used and there is now good evidence that children are experiencing adverse outcomes because of fluid treatment. The aim of this trial is to determine which intravenous fluid is best in children. It will be the largest and most relevant intravenous fluid trial performed in children. The results will have an immediate impact on treating children worldwide.Read moreRead less
Lung Injury: Influence Of Sodium, Water, Albumin, Gravity And Body Position
Funder
National Health and Medical Research Council
Funding Amount
$117,331.00
Summary
Although patients with poor oxygenation often require mechanical ventilation, only therapies that reduce lung damage improve outcome whereas therapies that improve oxygenation have not been shown to improve outcome. This project will examine the role of two common interventions in critically ill patients, fluid resuscitation and posture change, on lung injury. It is anticipated this will lead to clinical trials that will further improve survival in ventilated patients with respiratory failure.
Fluid intake is essential for survival. Disorders of thirst whether they be excessive or inadequate have dire conseqences as evidenced in recent heat waves in Europe and Indiawhere thousands of lives were lost primarily in the elderly whose thirst mechanisms are often disrupted. The excessive fluid intake, seen in psychotic disorders such as schizophrenia, is equally damaging. Much of the research over the last 50 years has concentrated on the hypothalamic regulation of thirst. This project will ....Fluid intake is essential for survival. Disorders of thirst whether they be excessive or inadequate have dire conseqences as evidenced in recent heat waves in Europe and Indiawhere thousands of lives were lost primarily in the elderly whose thirst mechanisms are often disrupted. The excessive fluid intake, seen in psychotic disorders such as schizophrenia, is equally damaging. Much of the research over the last 50 years has concentrated on the hypothalamic regulation of thirst. This project will attempt, for the first time, to define the location in the cerebral cortex of the drive to ingest water (perception of thirst).Read moreRead less
Open-label Randomised Trial Of Tolvaptan Versus Fluid Restriction In Hospitalised Patients With Moderate-severe Hyponatraemia
Funder
National Health and Medical Research Council
Funding Amount
$132,743.00
Summary
Low blood sodium level, known as hyponatraemia, is the most common electrolyte problem. It occurs in 15% of hospital patients, and can cause confusion, seizure and fatal brain swelling. Standard treatment for hyponatraemia is limiting oral fluid, but this is slow and not always effective. The drug tolvaptan works in mild hyponatraemia, but hasn't been formally tested in severe cases. We will compare benefits and risks of tolvaptan versus fluid restriction in patients with severe hyponatremia.