Intracellular Survival Of Burkholderia Pseudomallei And Evasion Of Autophagy
Funder
National Health and Medical Research Council
Funding Amount
$450,799.00
Summary
Melioidosis is a disease with high mortality that is caused by the bacterium Burkholderia pseudomallei. Autophagy is a natural part of the mammalian immune system. This project seeks to explain how Burkholderia pseudomallei avoids killing by host autophagy and identify the bacterial factors necessary for its survival within cells. The identified genes will be future targets for medical intervention.
In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin ....In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes. This project will investigate the mechanisms responsible for beta-cell failure in a mouse model with a similar time-dependent progression to obesity and type 2 diabetes as that seen in humans. C57BL-KsJ db-db mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity. With age, there are also a reduced number of beta-cells because of increased cell death. db-db mice will be studied at different stages in their natural progression to diabetes to fully characterise the secretory dysfunction and the changes in beta-cell phenotype over the time-course of diabetes development. The use of laser capture microdissection will allow us to study selectively the actual beta-cells without contamination from the other cells of the pancreas. The mice will also be treated with an agent that lowers blood glucose levels without affecting lipids to test the influence of hyperglycaemia itself in the development of beta-cell dysfunction. We will also test if the changes observed in the mice are regulated independently by high glucose levels in cell culture systems. The role of one candidate protein called ID-1 will be investigated as a potential link between hyperglycaemia and the development of beta-cell dysfunction.Read moreRead less
Characterisation Of A Type V Secretion In Escherichia Coli And Determining Its Role In Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$73,195.00
Summary
Disease causing bacteria assemble secretion systems to assist with colonisation, persistence and destruction of host tissue. These systems have been categorised as Type I to Type VI. A comprehensive understanding of these secretion systems, is of paramount importance for a complete understanding of bacterial pathogenesis. We will investigate the role of a novel Type V secretion system conserved amongst many human pathogens.
The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the Australians suffering the disease. While there is a well-established relationship between obesity and insulin resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic beta-cells compensate with enhanced insulin secretion. It is the failure of beta-cell compensation that is fundamental to the development of diabetes. The beta-cell is a highly spec ....The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the Australians suffering the disease. While there is a well-established relationship between obesity and insulin resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic beta-cells compensate with enhanced insulin secretion. It is the failure of beta-cell compensation that is fundamental to the development of diabetes. The beta-cell is a highly specialised cell with a unique metabolic profile and differentiation specifically geared towards making these cells able to sense fluctuations in circulating glucose levels and secrete insulin accordingly. We propose that in susceptible individuals, a gradual rise in blood glucose (hyperglycaemia) and lipid levels resulting from increasing obesity and insulin resistance leads to a loss of the unique expression pattern of genes necessary for appropriate insulin secretion. This exacerbates hyperglycaemia, which causes further beta-cell dedifferentiation and eventually the death of beta-cells by apoptosis. We have recently found evidence in several models of diabetes that supports this hypothesis. We propose to use animal studies and cell culture systems to investigate the following hypotheses important for our understanding of beta-cell failure and progression to diabetes: 1) The loss of beta-cell phenotype (dedifferentiation) underlies the loss of insulin secretory function in failing beta-cells. 2) Hyperglycaemia plays a critical role regulating the progression to beta-cell dedifferentiation. 3) The overexpression of key candidate gene products play an integral role linking hyperglycaemia to the loss of beta-cell secretion. 4) Endoplasmic reticulum stress is necessary for beta-cell death in diabetes. Our studies will make a major contribution to our understanding of why beta-cells fail in diabetes and aim to provide novel therapeutic targets in the treatment of diabetes.Read moreRead less
Investigation Of The Roles Of Protein Kinase C Epsilon In Insulin Secretion And Insulin Clearance
Funder
National Health and Medical Research Council
Funding Amount
$627,148.00
Summary
The rise in blood insulin levels after a meal normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized in part by a failure of the pancreas to produce adequate insulin in response to increases in blood sugar. This loss of insulin secretion has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. We have recently found that mice lacking a specific enzym ....The rise in blood insulin levels after a meal normally reduces blood sugar levels by increasing glucose uptake and storage in certain tissues, especially muscle. Type 2 diabetes is characterized in part by a failure of the pancreas to produce adequate insulin in response to increases in blood sugar. This loss of insulin secretion has been strongly linked to increases in the availability of fat, although the reasons for this are not clear. We have recently found that mice lacking a specific enzyme (protein kinase C epsilon) are much less susceptible to the problems in dealing with blood sugar that are caused by a high fat diet. We showed that this is due partly to improved insulin secretion, and also to a slower breakdown of insulin by the liver, which increases its availability to target tissues. The aim of this project is to investigate the mechanisms occurring in the liver and in the pancreas by which this enzyme contributes to improved insulin action. Firstly, we will examine insulin uptake in liver cells, to investigate how the enzyme controls this process. Secondly, we will determine the mechanism through which the activation of the enzyme, upon increased fat supply to pancreatic beta-cells, reduces insulin secretion in response to glucose. Finally, will assess the relative importance of these two actions of the enzyme in improving the control of blood sugar levels. This work will lead to a better understanding of the mechanisms by which fat oversupply, and hence obesity, can play a role in the development of Type 2 diabetes, so that they can be targeted both for the development of new and more effective treatments for the disorder and for prevention of its onset.Read moreRead less
Alterations In Secretion And Gene Expression In Pancreatic Beta Cells Exposed To Lipid.
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The project is aimed at a better understanding of the way in which fats control gene expression in the pancreatic beta cells of the islets of Langerhans. Because changes in gene expression are to likely to explain why exposure of these cells to fat disrupts their ability to release insulin, identification of these genes could explain why only some obese people develop Type 2 diabetes.
IL-22 As A Suppressor Of Pancreatic ?-Cell Stress And A Treatment For Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$854,490.00
Summary
Type 2 diabetes occurs when pancreatic beta cells fail to produce enough insulin to control blood sugar levels. We have discovered that the IL-22 protein produced by immune cells protects beta cells from stress. Diabetic mice given IL-22 show restored control of blood sugar levels. The proposed research will take steps to safely introduce IL-22 based therapy into the clinic and gain a deeper understanding of the mechanisms of action of IL-22.
Correlative Structure-function Studies Of Cis- And Trans-Golgi Membrane Traffic In Mammalian Cells
Funder
National Health and Medical Research Council
Funding Amount
$649,531.00
Summary
This project combines imaging by light and electron microscopy with additional techniques for studying protein function at the molecular level, to elucidate how changes in the 3D organisation of cellular machinery can lead to fundamental changes in the function and health of mammalian cells. Although this work includes detailed investigation of the 'insulin factory', it has the potential to modify established concepts on membrane traffic and protein secretion well beyond the field of diabetes.
Therapeutic Strategies And Screening Methods For PKC Epsilon Antagonists In The Treatment Of Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$157,375.00
Summary
Type 2 diabetes is a chronic disease affecting over a million Australians and hundreds of millions of people worldwide. Its prevalence is rising due to several factors such as an increase in caloric intake, the aging of the population, and the common sedentary lifestyle of Western civilization. Type 2 diabetes occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and has been strongly linked to obesity. We have now shown ....Type 2 diabetes is a chronic disease affecting over a million Australians and hundreds of millions of people worldwide. Its prevalence is rising due to several factors such as an increase in caloric intake, the aging of the population, and the common sedentary lifestyle of Western civilization. Type 2 diabetes occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and has been strongly linked to obesity. We have now shown that an enzyme found in the pancreas becomes inappropriately activated under conditions of fat oversupply, and plays an important role in the development of defects in insulin release from the pancreas in response to glucose. Excitingly, we have also shown that inhibition of this enzyme can partly reverse these defects once they have been established. We now intend to further validate this enzyme as a drug target by determining the optimum dosing regimen for the treatment of type 2 diabetes in a mouse model, and testing whether this approach can be used in conjunction with previously-developed drugs which promote insulin action, to improve bood glucose handling better than either treatment alone. This would promote the enzyme as a therapeutic strategy in the treatment of Type 2 diabetes. We also plan to develop a high throuhput screen to identify novel inhibitors of the enzyme, which will further increase the attractiveness of the project to pharmaceutical companies, who are better able to implent full commercialization of our findings.Read moreRead less
Effect Of Oral Glutamine On GLP-1 And Insulin Secretion And Glycaemia In Humans.
Funder
National Health and Medical Research Council
Funding Amount
$397,444.00
Summary
Diabetes is an ever increasing problem with serious complications. We will investigate whether glutamine, one of the most common amino acids (protein building blocks) in the body, has a beneficial effect on blood glucose and insulin levels in the body in people who have type 2 (non-insulin dependent) diabetes. If so, glutamine supplementation may represent a novel, cheap and palatable way of improving outcomes and preventing the development of complications in people with type 2 diabetes.