Protein Kinases Regulate Salt Reabsorption In The Kidney
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney. When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way that they are able to do this has profound implicat ....This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney. When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way that they are able to do this has profound implications for human heart and kidney disease, and biology in general.Read moreRead less
The Roles Of Ion Transporters In Sulfate Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$443,450.00
Summary
Sulfate is an essential nutrient for life. Individuals with autism, Alzheimers, Parkinsons and motor neurone disease have low blood sulfate levels. In this project, we plan to study several genes as candidates in controlling blood sulfate levels. We also plan to determine the role blood sulfate levels play in longevity. Our findings will make an important link between dietary nutritional intake, genes, blood sulfate levels and longevity.
The Role Of Peroxisome Proliferator Activated Receptor Gamma In Sodium Transport In Human Proximal Tubule Cells
Funder
National Health and Medical Research Council
Funding Amount
$566,946.00
Summary
Renal failure accounts for a considerable component of the excess morbidity and mortality observed in patients with diabetes mellitus. In addition, the emotional, social and cost to the community of dialysis is enormous. PPARgamma is activated by drugs that have been recently introduced for the treatment of type 2 diabetes mellitus. The propensity for these drugs to cause fluid retention has emerged recently as the most common serious adverse drug reaction associated with these compounds. the de ....Renal failure accounts for a considerable component of the excess morbidity and mortality observed in patients with diabetes mellitus. In addition, the emotional, social and cost to the community of dialysis is enormous. PPARgamma is activated by drugs that have been recently introduced for the treatment of type 2 diabetes mellitus. The propensity for these drugs to cause fluid retention has emerged recently as the most common serious adverse drug reaction associated with these compounds. the definitive cause of fluid retention with the use of PPAR gamma agonists is not known. Studies reported in the last 12 - 18 months have suggested that a common pathway may be involved in the development of the fluid retention, the high blood pressure and the scarring that occurs in the kidney. This project will be the first to provide a comprehensive examination of the effect of PPARgamma induction on renal sodium absorption and fluid retention in the human proximal tubule cells and the potential molecular mechanisms underlying them. This will provide insight as to potential adjuvant treatments for patients with diabetes.Read moreRead less
Phenotypic Studies Of The NaSi-1 Transporter Knock-out Mouse
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
Sulfate is an essential nutrient for cell growth and survival. Despite this, sulfate levels are rarely measured clinically and very little is known about the consequences of disturbed blood sulfate levels.The human kidneys regulate sulfate levels in the body, by mechanisms that are not fully characterised. Our laboratory has isolated a gene (Nas1) from humans and mice, which encodes a protein involved in sulfate absorption from the diet. Nas1 also controls sulfate excretion into the urine, by re ....Sulfate is an essential nutrient for cell growth and survival. Despite this, sulfate levels are rarely measured clinically and very little is known about the consequences of disturbed blood sulfate levels.The human kidneys regulate sulfate levels in the body, by mechanisms that are not fully characterised. Our laboratory has isolated a gene (Nas1) from humans and mice, which encodes a protein involved in sulfate absorption from the diet. Nas1 also controls sulfate excretion into the urine, by regulating kidney reabsorption. Normally, very little sulfate is lost in the urine. However, individuals with autism, Alzheimers, Parkinsons, motor neurone disease and liver cirrhosis, have been reported to have reduced blood sulfate levels. The mechanisms underlying the low blood sulfate levels in these disorders, have not been characterised. Recently, we generated a mouse lacking the Nas1 gene. This mouse has very low blood sulfate levels and suffers from growth retardation, reduced fertility and displays seizures. In this study, we plan to investigate these phenomena in the Nas1 knock out mouse and determine the role of low blood sulfate levels on these conditions. We also plan to characterise the role of low blood sulfate levels on the expression of genes in various body organs, using a gene array approach. In addition, we plan to study wound repair and the detoxification process in our Nas1 knock out mouse, which we expect to be affected due to low blood sulfate levels. These studies will establish the roles sulfate plays in mammalian physiology and will provide a foundation for studying diseases that are associated with changes in blood sulfate levels.Read moreRead less
TRAFFICKING OF MEMBRANE SULFATE TRANSPORTERS IN THE KIDNEY
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Many diseases such as diabetes, cystic fibrosis, Alzheimer's and Parkinson's, results from a defect in the intracellular trafficking of specific membrane proteins. One important family of membrane proteins are the renal sulphate transporters, NaSi-1 and sat-1. They are two important proteins that control body sulphate homeostasis. Sulphate in the body is essential for cell matrix formation and cartilage-bone development and growth. Trafficking defects in these proteins can lead to changes in ser ....Many diseases such as diabetes, cystic fibrosis, Alzheimer's and Parkinson's, results from a defect in the intracellular trafficking of specific membrane proteins. One important family of membrane proteins are the renal sulphate transporters, NaSi-1 and sat-1. They are two important proteins that control body sulphate homeostasis. Sulphate in the body is essential for cell matrix formation and cartilage-bone development and growth. Trafficking defects in these proteins can lead to changes in serum sulphate levels, which results in softening of the bones, insufficient cartilage development, and changes in many metabolic processes. Using techniques of molecular and cellular biology, we aim to identify the precise the mechanisms that control the trafficking of these proteins in cells. This will enable us to determine how these proteins functions in both the normal and diseased states, which is currently unknown.Read moreRead less