Endothelial And Mesenchymal Cell Interactions In Pancreatic Beta Cell Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$95,583.00
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.
A Preclinical Model Of Pig Islet Xenotransplantation As Treatment For Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$4,380,000.00
Summary
The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-sec ....The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-secreting tissue can avoid the aggressive rejection response that occurs with xenographs and provide normal blood glucose control without insulin. This project concentrates on the five main issues that need to be overcome before pig insulin-secreting tissue can be used in diabetics. These are: identifying the best source of insulin secreting tissue to use; adult islets, newborn or foetal islet cell clusters; overcoming the strong rejection response to pig tissue; identifying a safe and effective immunosuppressive regime; producing a new types of genetically modified pigs that will provide islets tissue that will work in humans; and demonstrating that pig islet transplantation will not pose undue infective risks for the patient or community. This truly collaborative program grant has brought together a large group of investigators with strong research records in diabetes, islet transplantation, xenotransplantation, pig transgenesis and pig genetics and includes scientists and clinicians who look after diabetic patients. Unique pig resources will be used including genetically manipulated pigs that have been shown to avoid some of the rejection mechanisms associated with transplanting pig tissue. There is a captive-bred baboon colony that provided a unique model of diabetes. A world class pig transgenesis facility has been enlisted to generate new lines of genetically altered pigs as new data is produced within the group. Finally because of the involvement of the National Pancreas Transplant Unit any proven therapeutic strategy can be brought quickly to clinical trials.Read moreRead less
Prevention Of Pancreatic Beta Cell Destruction In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$621,458.00
Summary
Associate Professor Helen Thomas is a molecular and cell biologist with a particular interest in pancreatic islet biology, studying the mechanisms of pancreatic beta-cell destruction in diabetes. The aim of this work is to develop strategies to protect these cells. Such protection will improve our ability to preserve beta-cell mass in type 1 and type 2 diabetes, and after islet transplantation.
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.
The Preferential Release Of Young Insulin Secretory Granules.
Funder
National Health and Medical Research Council
Funding Amount
$670,005.00
Summary
The aim of this study is to investigate the cause of reduced glucose induced insulin secretion in type 2 diabetes. In pancreatic beta-cells, insulin is packaged and stored in secretory granules (SGs). Upon stimulation, these SGs deliver insulin to the bloodstream. It is known that insulin SGs exist in two functionally distinct pools; and one pool is preferentially secreted upon stimulation. How a cell can differentiate the two SG pools is unclear, and we will address this issue in this project.
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.
Elucidating The Pathogenic Role Of Rotavirus Infection In Type 1 Diabetes Development
Funder
National Health and Medical Research Council
Funding Amount
$535,579.00
Summary
Rotavirus infection is the main cause of severe diarrhoea in children, and has been implicated in accelerated progression of genetically at-risk children towards type 1 diabetes in two independent studies. My group has further discovered that rotavirus also accelerates diabetes onset in mice in a novel immunological process. In this project, we will determine the mechanism behind this disease exacerbation in the mice, to facilitate understanding of the process in children.
Metabolically Reprogramming The Stroma To Starve Pancreatic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$598,848.00
Summary
Pancreatic cancer claims five Australian lives every day. Despite aggressive treatment regimes, there has been no improvement in patient survival in the last decade. Evidence suggests that targeting cancer cells alone is not enough. Pancreatic tumours are surrounded by an extensive scar tissue reaction (stroma). This intense stromal reaction inhibits drug delivery and increases tumour growth. Thus, decreasing the stroma is a potential therapeutic strategy and is the focus of this proposal.
Which Transgenic Pig Will Be Used For Islet Transplantation In Humans?
Funder
National Health and Medical Research Council
Funding Amount
$3,031,083.00
Summary
We propose that xenotransplantation of pig islets will cure Type 1 diabetes. This program will generate genetically modified pigs to overcome the molecular differences between pigs and humans by removing a pig gene and inserting several human genes. In addition, we will add immunosuppressive genes and so minimise the need for drug treatment of the diabetic recipient. We will test our hypothesis by transplanting islets from these genetically modified pigs into baboons. We suggest that this will p ....We propose that xenotransplantation of pig islets will cure Type 1 diabetes. This program will generate genetically modified pigs to overcome the molecular differences between pigs and humans by removing a pig gene and inserting several human genes. In addition, we will add immunosuppressive genes and so minimise the need for drug treatment of the diabetic recipient. We will test our hypothesis by transplanting islets from these genetically modified pigs into baboons. We suggest that this will provide an inexhaustible supply of islets for transplantation.Read moreRead less