Characteristics Of Splice Variants Of The Skeletal Muscle Ryanodine Receptor: Implications For Myotonic Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and ....The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and locomotion depend on the release of calcium ions from stores inside muscle cells. Ryanodine receptor calcium channels regulate calcium release from the stores. The essential nature of ryanodine receptors is underlined by death at or before birth when ryanodine receptor expression is defective. In addition genetic defects in the ryanodine receptor cause cardiac arrhythmias, malignant hyperthermia and central core disease. Ryanodine receptor function is compromised in heart failure and fatigue. The essential role of ryanodine receptors makes them a potential therapeutic target, but they are not used in this way because of our limited knowledge of the protein. Myotonic dystrophy is an autosomal dominant multi-system disorder, in which an expansion of non-coding DNA leads to changes in expression of several different proteins. Although the genetic basis of myotonic dystrophy is now reasonably well understood, the contribution of molecular changes in the affected proteins to the myopathy has not been investigated. Our group has recently discovered that the juvenile form of the ryanodine receptor protein is highly expressed in adults suffering from myotonic dystrophy. By discovering more about the properties of the juvenile isoform, we will understand more about the basic mechanisms of ryanodine receptor function in developing muscle and in myotonic dystrophy and be able to design drugs to specifically modify ryanodine receptor activity.Read moreRead less
Regulation Of Pancreatic Beta-cell Number And Function By Adipocyte-released Hormones, Free Fatty Acids And Ghrelin.
Funder
National Health and Medical Research Council
Funding Amount
$256,500.00
Summary
The disease diabetes mellitus comprises a heterogeneous group of disorders all characterised by high blood glucose levels. Beta-cells in the pancreas, which secrete insulin, are central to the pathophysiology of the disease. Type 1 or insulin-dependent diabetes mellitus results from an absolute deficiency of insulin due to auto immunological destruction of the pancreatic beta cell, and accounts for 5-10% of total diabetes mellitus. In the more common type 2 or non-insulin-dependent diabetes mell ....The disease diabetes mellitus comprises a heterogeneous group of disorders all characterised by high blood glucose levels. Beta-cells in the pancreas, which secrete insulin, are central to the pathophysiology of the disease. Type 1 or insulin-dependent diabetes mellitus results from an absolute deficiency of insulin due to auto immunological destruction of the pancreatic beta cell, and accounts for 5-10% of total diabetes mellitus. In the more common type 2 or non-insulin-dependent diabetes mellitus, liver, muscle and fat cells are resistant to the action of insulin and compensatory mechanisms that are activated in the beta-cell to increase insulin secretion are not sufficient to maintain normal blood glucose levels. In Western countries including Australia, type 2 diabetes currently affects around 2% of the whole population and about 6% of adults (10% of over 60-y) and continues to grow at around 6% per annum. Type 2 diabetes often occurs in obese patients and a direct link between obesity and type 2 diabetes has been strongly suggested by research to date. It has also been found that a progressive loss of beta-cell function throughout the course of the disease results in the reduction of insulin secretion. The contribution of excessive fat tissue in obese patients to the progress of type 2 diabetes is not clear. Certain hormones from fat cells, metabolic regulatory hormone, and fatty acids have been demonstrated to influence the function of beta-cells in previous studies, including our own. We now aim to investigate in detail the effect of these on cultured beta-cells with molecular and cell biology techniques. We expect to identify a factor or factors which stimulate or inhibit the progress of beta-cell dysfunction, with the potential to identify therapeutic targets in the treatment of type 2 diabetes.Read moreRead less
Type 2 diabetes is reaching epidemic proportions across the world and is a huge burden in health care costs. We know it is a multifaceted disease with many symptoms, one of which is a reduction in insulin secretion. This proposal sets out to determine the mechanisms of insulin secretion from healthy tissue and what goes wrong in disease.