L-amino Acid Sensing By The Extracellular Calcium-sensing Receptor: Molecular, Cellular And In Vivo Studies
Funder
National Health and Medical Research Council
Funding Amount
$362,545.00
Summary
Recent work by Dr Conigrave and colleagues demonstrates for the first time that protein and calcium metabolism are linked at the molecular level by the widely distributed calcium-sensing receptor. The project will aim to demonstrate the physiological significance of this finding by testing whether L-amino acids, the building blocks of body protein, exert receptor-dependent control over the secretion and blood levels of hormones that regulate body calcium levels. It will further test the hypothes ....Recent work by Dr Conigrave and colleagues demonstrates for the first time that protein and calcium metabolism are linked at the molecular level by the widely distributed calcium-sensing receptor. The project will aim to demonstrate the physiological significance of this finding by testing whether L-amino acids, the building blocks of body protein, exert receptor-dependent control over the secretion and blood levels of hormones that regulate body calcium levels. It will further test the hypothesis by determining whether amino acids exert receptor-dependent control over the proliferation of bone forming cells and urinary excretion of calcium.Read moreRead less
Nutrient Dependent Signalling In Bone Via Calcium Sensing Receptors
Funder
National Health and Medical Research Council
Funding Amount
$226,650.00
Summary
Osteoporosis is a major health problem that affects as many as 10% of the Australian Community and costs the health budget millions of dollars each year. A number of key nutritional factors including calcium and dietary protein intake are known to be important in the development of osteoporosis. This proposal will test the hypothesis that human bone cells express a protein which senses calcium and amino acids, the calcium-sensing receptor, and thereby respond to nuritional signals arising from t ....Osteoporosis is a major health problem that affects as many as 10% of the Australian Community and costs the health budget millions of dollars each year. A number of key nutritional factors including calcium and dietary protein intake are known to be important in the development of osteoporosis. This proposal will test the hypothesis that human bone cells express a protein which senses calcium and amino acids, the calcium-sensing receptor, and thereby respond to nuritional signals arising from the presence of calcium ions and amino acids in plasma. Furthermore, we propose that by promoting osteoblast proliferation, maturation and survival, the calcium sensing receptor acts as the key molecular mechanism by which dietary calcium and protein promotes bone formation.These studies have potential to explain relationships between bpne resorptive activity, which raises local calcium concentrations, and bone formation activity and the coupling of bone forming and resorbing activity. These studies have the potential to explain the positive effects of calcium and protein intake on bone mass and may also shed light on the regulation of the coupling between osteoblastic and osteoclastic activityRead moreRead less
Inhibition Of Glucose-stimulated Insulin Secretion By Protein Kinase C Epsilon
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
Type 2 diabetes is a chronic disease which occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and is strongly linked to obesity. We have discovered that fat oversupply activates an enzyme in the pancreas causing defects in insulin release due to glucose. Inhibiting this enzyme helps overcome diabetes, through poorly defined mechanisms that we aim to clarify here. Our work could lead to new therapies for diabetes.
The Role Of Muscle Fatty Acid Oxidation In Regulating Intramyocellular Lipid Accumulation.
Funder
National Health and Medical Research Council
Funding Amount
$169,695.00
Summary
Obesity and the subsequent accumulation of fat in muscle leads to reduced insulin action and an increased risk of type 2 diabetes. This project will investigate the metabolic processes that influence fat accumulation and oxidation primarily in skeletal muscle, the tissue responsible for most fuel utilization in the body. This information will help design therapeutic strategies to prevent the development of type 2 diabetes.
Genetic Programs Induced By The Nuclear Hormone Receptor PPARdelta In Muscle: Control Of Lipid And Energy Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of d ....Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of dyslipidemia by mediating cholesterol efflux from tissues. In contrast, the LDLs accumulate in the arterial wall leading to atherosclerosis. Physiological maintenance of lipid homeostasis requires a dynamic balance between metabolic signalling cascades, diet, lifestyle etc. PPPARs are nuclear hormone receptors that function as fatty acid activated transcription factors that regulate lipid and cholesterol homeostasis. PPARs are bona fide targets for the development of therapeutic compounds useful in the treatment of lipid disorders. PPAR delta is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Muscle is a major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile and lipid metabolism. Understanding the functional role of PPAR delta in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body lipid homeostasis. Understsanding these receptors may provide a pharmaceutical solution for the prevention of hyper-lipidemia--cholesterolemia, and atherogenic disease. Moreover, it may lead to the identification of agents that influence a major mass tissue in terms of lipid absorption, and increased fatty acid oxidation, and consequently normalize the blood lipid profile.Read moreRead less