Secretion is an essential step in memory and learning, control of metabolism and reproduction and the functioning of most organs. Secretory dysfunction also underlies many diseases including type 2 diabetes. We plan experiments to test for a new model of control of insulin secretion.
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
Fine Mapping And Characterisation Of Polymorphic Immunoregulatory Genes In The Central MHC
Funder
National Health and Medical Research Council
Funding Amount
$529,656.00
Summary
The major histocompatibility complex (MHC) is a group of genes that is usually inherited as a block. The group includes the HLA genes which can serve as markers for neighbouring genes that are less well characterised. For example, some variant forms (polymorphisms) of the HLA genes mark differences in susceptibility to diabetes, lupus and IgA deficiency. We propose that this may be caused by variations in the neighbouring uncharacterised genes affecting control of persistent inflammation of vari ....The major histocompatibility complex (MHC) is a group of genes that is usually inherited as a block. The group includes the HLA genes which can serve as markers for neighbouring genes that are less well characterised. For example, some variant forms (polymorphisms) of the HLA genes mark differences in susceptibility to diabetes, lupus and IgA deficiency. We propose that this may be caused by variations in the neighbouring uncharacterised genes affecting control of persistent inflammation of various target organs. Evidence so far suggests a gene in the central MHC may be responsible. In this project we will study DNA from patients who have unusual combinations of HLA and other MHC genes, to further define which part of the MHC contains the critical immunoregulatory genes. Most genes in the MHC have now been identified by the Human Genome Project, so we will be able to select the most promising candidates in the region of interest. We will then use DNA of known HLA types to determine if the candidate genes vary between individuals. The function of interesting genes will then be investigated by creating cell lines carrying part of the gene in the reverse (anti-sense) orientation. This generates a reverse messenger (m) RNA which binds the normal mRNA and prevents synthesis of the protein. We will then examine which responses of the resultant cell lines are abnormal (eg: production of inflammatory mediators or cytokines). Having elucidated the functions our genes, we will overexpress each version that occurs in patients in cultured cells and look for differences in function. In parallel with this work, we will use laboratory mice with known combinations of MHC genes to establish the effects of particular genes in a live animal.Read moreRead less
Genotypes And Phenotypes Of Human Primary Non-congenital Antibody Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$544,692.00
Summary
Antibodies represent a key component of the immune system, and a particularly important in defence against bacterial and viral infections. In some individuals, antibody production fails, rendering them more susceptible to infection. In most cases, the mechanism of antibody failure is unknown. This project seeks to determine the genetic and cellular mechanisms of antibody failure. This could improve diagnosis for immune deficiency, and improve our overall understanding of the immune system.
Role For Zinc And ZIP2 In The Action Of Nitric Oxide And In Vascular Protection Against Cigarette Smoke And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$685,941.00
Summary
The NO/cGMP signalling pathway, which is central to cardiovascular physiology and protection against disease, is only fully effective when there are adequate levels of zinc in the vascular endothelium. This is especially important where zinc stores are depleted (elderly, smokers, diabetics and kidney disease). There is an urgent clinical need to implement strategies to monitor vascular Zn status. This application will explore the underlying science and translate these to the clinic.
Defining The Role Of Zinc At The Host-pneumococcal Interface
Funder
National Health and Medical Research Council
Funding Amount
$870,925.00
Summary
Streptococcus pneumoniae is the world’s foremost bacterial pathogen. In Australia, bacterial infections are responsible for more than 9000 deaths every year, and the economic burden associated with treating diseases arising from pneumococcal infections is more than $1 billion annually. This proposal aims to define the role of the transition metal zinc in innate immune resistance to bacterial infection. This knowledge will reveal new targets for next generation antimicrobial therapeutics.