Identification Of The Mechanisms Of Lipotoxicity Within The Bone Marrow Milieu
Funder
National Health and Medical Research Council
Funding Amount
$416,007.00
Summary
Obesity and osteoporosis two major epidemics of our time. Bone and fat communicate with each other in two different ways. A hormonal communication links bone and fat in a positive manner. In contrast, at the local level, increasing levels of marrow fat with aging affect bone quality through the local release of toxic factors. We will identify these factors and will assess the potential reversibility of lipotoxicity in bone, as a new therapeutic approach to osteoporosis in the elderly.
Omega 3 Polyunsaturated Fatty Acid Analogues In The Treatment Of Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$418,446.00
Summary
Treatment of diabetes has become an even greater challenge to our community today. The ill health from diabetes arises from the high blood sugar levels. Treatment of diabetic complications such as kidney damage has now become a major goal. This research addresses this problem by trying to find out if a group of novel polyunsaturated fatty acids can target the process initiated by high blood sugar responsible for kidney damage.
Targeting Insulin Hypersecretion To Prevent Type 1 And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$834,596.00
Summary
Diabetes develops when islet beta-cells fail to secrete insulin. While major differences exist in the mechanisms by which type 1 and type 2 diabetes develop, there is overlap in beta-cell susceptibility factors. We will investigate whether an islet 'overwork' response to excess nutrient loads underlies beta-cell susceptibility to failure in both types of diabetes. We will also develop novel pharmacological approaches to reduce islet 'overwork' to prevent and treat type 1 and 2 diabetes.
Role Of Islet ?-cell Failure In The Pathogenesis Of Non-alcoholic Steatohepatitis
Funder
National Health and Medical Research Council
Funding Amount
$560,111.00
Summary
Some people respond to obesity poorly developing diseases such as non-alcoholic steatohepatitis (NASH) and diabetes. Other people do not, safely storing the excess energy in non-abdominal fat. The applicants will study 2 obese strains of mice; one develops “adipose tissue restriction”, NASH and diabetes, the other does not. The hypothesis that failure of compensatory insulin secretion to over-nutrition is an upstream event causing adipose tissue restriction, followed by NASH, will be tested.
Ceramide Metabolism And ER Stress In Fatty-acid Mediated Destruction Of Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
The underlying cause of Type 2 diabetes is the failure of pancreatic beta cells to secrete sufficient insulin to overcome the insulin resistance that is associated with obesity. Beta cell failre is associated with both defective insulin secretion and loss of beta cell mass. This proposal focuses on the cellular mechanisms and stress pathways whereby too much fatty acid promotes beta cell death.
ERRgamma And Skeletal Muscle: Insights Into Lipid Utilization And Catabolism
Funder
National Health and Medical Research Council
Funding Amount
$357,936.00
Summary
The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the ....The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile, lipid metabolism and obesity. Understanding the functional role of the orphan ERR receptors in skeletal muscle in the context of inflammation, lipid and energy homeostasis is of paramount importance in further understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes and obesity. Identification of novel ERRgamma targets that regulate metabolism in a major mass peripheral tissue, and positively influence the risk factors for cardiovascular disease, provides platforms for potential therapeutic intervention. Cardiovascular disease is the foremost cause of global mortality, and was responsible for >15 million deaths in 2003.Read moreRead less
Mechanisms Of PKCepsilon-dependent Regulation Of Beta-cell Lipid Metabolism And Insulin Secretion
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
Lipid loading of the insulin-producing beta cells of the pancreas contributes to the onset of Type 2 diabetes, but the mechanisms are poorly understood. We have recently established that inhibiting the enzyme PKCe helps restore insulin secretion. By better defining the cellular role of PKCe we will clarify how insulin secretion is disrupted by fatty acids and cholesterol.
NR1 Nuclear Hormone Receptors, And Skeletal Muscle Metabolism: Insights Into Dyslipidemia And Metabolic Disease.
Funder
National Health and Medical Research Council
Funding Amount
$582,547.00
Summary
The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). Orphan NR1 receptors are abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeost ....The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). Orphan NR1 receptors are abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight, and energy expenditure. Muscle is the 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, lipid metabolism and obesity. Understanding the functional role of the orphan NR1 receptors in skeletal muscle in the context of inflammation, lipid and energy homeostasis is of paramount importance in further understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes and obesity. Identification of novel NR1 targets that regulate metabolism in a major mass peripheral tissue, and positively influence the risk factors for cardiovascular disease, provides platforms for potential therapeutic intervention. Cardiovascular disease is the foremost cause of global mortality, and was responsible for >15 million deaths in 2003.Read moreRead less