They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid ....They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid bodies (EB) - EB-derived cells, fetal pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth-differentiation factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic constructs allowing regulated expression of fluorescently-tagged marker genes and growth-transcription factors will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level, and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in people with type 1 diabetes.Read moreRead less
The Role Of Endoplasmic Reticulum (ER) Stress In Pancreatic Beta-cell Dysfunction.
Funder
National Health and Medical Research Council
Funding Amount
$85,775.00
Summary
Diabetes results from pancreatic ß-cell failure which is characterised by insulin secretory defects and ß-cell destruction. This is mediated by inflammatory cytokines in type 1 diabetes and by high levels of fat in type 2 diabetes. The mechanisms by which ß-cells fail remain to be clarified but they are important considering the current epidemic of diabetes in Australia. This project will enhance our understanding of ß-cell failure and may provide therapeutic targets for diabetes treatment.
Impact Of Beta Adrenergic Antagonsim On Energy Metabolism And Body Composition
Funder
National Health and Medical Research Council
Funding Amount
$118,557.00
Summary
Beta-blockers are drugs commonly used to treat high blood pressure, anxiety, migraines and irregular heart rhythms. They work by blocking the action of chemical messengers called catecholamines which increase metabolic rate, fat utilisation and heart function. The aim is to determine whether ?-blockers impair metabolic function of the body which may lead to obesity and a loss of fitness. Judicious use of these medications and consideration of alternatives may lead to better health outcomes.
Expansion, Differentiation And Functional Analysis Of In Vitro Derived Pdx1+ Pancreatic Progenitors
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Type 1 diabetes is a condition that arises when the body's immune system destroys insulin-producing beta cells within the pancreas. Recent studies have shown that normal glucose control can be restored by replacing the missing beta cells by transplantation of cells from deceased donors. However, the demand for transplant material outweighs supply. The work described in this application seeks to define how insulin-producing beta cells can be derived in the laboratory from embryonic stem cells .
Investigations Of Beta Cell Dysfunction And Death In Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$314,433.00
Summary
Diabetes is a disease that affects 100 million people worldwide and this number is expected to double in the next twenty years. This disease is characterised by high blood sugar levels which over prolonged periods of time can affect the function of the kidneys and eyes as well as causing heart attacks and strokes. A main contributing factor to diabetes is the inability of the pancreas to secrete insulin, the hormone that is responsible for keeping blood sugar levels in the normal range. The reas ....Diabetes is a disease that affects 100 million people worldwide and this number is expected to double in the next twenty years. This disease is characterised by high blood sugar levels which over prolonged periods of time can affect the function of the kidneys and eyes as well as causing heart attacks and strokes. A main contributing factor to diabetes is the inability of the pancreas to secrete insulin, the hormone that is responsible for keeping blood sugar levels in the normal range. The reason for this inability of the pancreas to secrete enough insulin is not known. It is known however, that both genetic and environmetal factors are responsible. The aim of this investigation is to determine the biochemical and genetic reason for decreased insulin secretion from an animal model of diabetes called DBA-2J mouse. Specifically we will be studying the effects of long-term increased sugar and fat on the function of the insulin producing cells of the pancreas, in order to identify the biochemical pathway responsible for reduced insulin secretion. In parallel we will be investigating the gene or genes in DBA-2J mice that are responsible for decreased insulin secretion and pancreatic cell death. This will provide clues as to the genes that may be responsible for diabetes in humans. This project will provide crucial information on the cause of reduced insulin secretion both at the cellular and genetic level, and will lead to a better understanding of the cause of diabetes.Read moreRead less
Osteoblast Control Of Mesenchymal Progenitor Cell Differentiation: The Role Of Glucocorticoids And Wnt Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$443,131.00
Summary
Osteoporosis is an important and growing health issue. Reduced ability to make new bone is an important cause of osteoporosis. In this project we will study how the immature cells which eventually make bone are recruited and controlled. In particular, we will study how genes coding for important growth factors are regulated so that the proper signals are sent to young cells to induce them to become bone-making rather than fat-making cells.
Aldosterone Mediated Cardiac Pathophysiology:The Role Of Corticosteroid Receptors And 11 HSD Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind ....Aldosterone a hormone that circulates in blood and is associated with cardiovascular disease. Recently, two clinical trials (RALES, EPHUSUS) demonstrate that if you stop this hormone from acting by giving drugs that inhibit it from binding to the receptor that mediates its response, there is an improvement in the health of heart failure patients. How aldosterone mediates its detrimental effects on heart is largely unknown. Glucocorticoids are another hormone that circulates in blood and can bind to the same receptor as aldosterone. In contrast to aldosterone glucocorticoids appear to play a basic maintenance role in heart. Our central hypothesis is that in the healthy heart aldosterone has minimal effects , however, in the diseased heart aldosterone associated pathophysiology is a result of both an increase in the ability of aldosterone to signal to cells and disruption of glucocorticoid signalling. This grant proposal will address how aldosterone and glucocorticoids may directly signal within cardiac cells and how this signalling changes in the diseased heart. In addition, we investigate if enzymes that metabolize glucocortioids and thus render them non-functional play a role in cardiac disease, and if we can reverse the detrimental effects of aldosterone by artificially increasing the production of glucocorticoids in heart. By understanding the mechanisms by which aldosterone promotes cardiac disease, and the role of glucocorticoids and their metabolism in this process will lead to a better understanding of aldosterone induced pathology and thus lead to novel therapeutic targets.Read moreRead less