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
Regulation Of Insulin Signalling And Glucose Homeostasis By Protein Tyrosine Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
A common feature of type 2 diabetes is high blood glucose due to peripheral insulin resistance. Protein tyrosine phosphatases (PTPs) that antagonise insulin signalling might be important targets for therapeutic intervention in type 2 diabetes; inhibition of specific PTPs may allow for enhanced IR signalling to alleviate insulin resistance. This proposal will examine the roles of PTPs and in particular TCPTP in insulin signalling and glucose homeostasis.
Novel Regulators Of Glucose Metabolism And Inflammation In Adipose Tissue Of Females
Funder
National Health and Medical Research Council
Funding Amount
$282,830.00
Summary
Obesity is a common problem which can lead to development of diabetes and heart disease. One of the major mechanisms by which obesity leads to these diseases involves a defect in the ability of insulin to stimulate uptake of glucose into cells. We have found that excess of the sex hormone testosterone in women can contribute to this defect in tissues. This study will investigate why testosterone causes this defect in females and whether this defect can be prevented using existing drug therapies.
I am a cellular physiologist investigating the role of ion channels, receptors and intracellular signalling systems in the control of hormone secretion from endocrine cells, contraction of cardiac myocytes and to a lesser extent, growth of endometrium can
The Effect Of PKC Epsilon On The Insulin Receptor And Whole Body Glucose Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$82,261.00
Summary
Increased fat availability is strongly associated with insulin resistance and type 2 diabetes. Data from this lab has shown animals lacking a particular enzyme (Protein Kinase C epsilon) are able to compensate for this insulin resistance and maintain normal blood glucose levels by elevating insulin availability, with a major site of action being the liver. This project therefore aims to examine the action of PKC epsilon on insulin clearance by the liver.
Defining The Insulin-signalling Defect In Human Insulin Resistance And Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$94,280.00
Summary
Problems with the way insulin removes glucose from the circulation contribute to developing type 2 diabetes. Despite research to date, controversy remains regarding the nature of known defects in insulin action and their relevance to humans. We plan to measure molecules involved in insulin action in muscle of people with insulin resistance, which is linked to diabetes. These studies will define new defects that cause insulin resistance and type 2 diabetes in humans.
Nutrient Dependent Signalling In Bone Via Calcium Sensing Receptors
Funder
National Health and Medical Research Council
Funding Amount
$226,650.00
Summary
Osteoporosis is a major health problem that affects as many as 10% of the Australian Community and costs the health budget millions of dollars each year. A number of key nutritional factors including calcium and dietary protein intake are known to be important in the development of osteoporosis. This proposal will test the hypothesis that human bone cells express a protein which senses calcium and amino acids, the calcium-sensing receptor, and thereby respond to nuritional signals arising from t ....Osteoporosis is a major health problem that affects as many as 10% of the Australian Community and costs the health budget millions of dollars each year. A number of key nutritional factors including calcium and dietary protein intake are known to be important in the development of osteoporosis. This proposal will test the hypothesis that human bone cells express a protein which senses calcium and amino acids, the calcium-sensing receptor, and thereby respond to nuritional signals arising from the presence of calcium ions and amino acids in plasma. Furthermore, we propose that by promoting osteoblast proliferation, maturation and survival, the calcium sensing receptor acts as the key molecular mechanism by which dietary calcium and protein promotes bone formation.These studies have potential to explain relationships between bpne resorptive activity, which raises local calcium concentrations, and bone formation activity and the coupling of bone forming and resorbing activity. These studies have the potential to explain the positive effects of calcium and protein intake on bone mass and may also shed light on the regulation of the coupling between osteoblastic and osteoclastic activityRead moreRead less
Role Of The Growth Hormone Binding Protein As A Transcriptional Activator
Funder
National Health and Medical Research Council
Funding Amount
$387,226.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, wh ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, where it can directly activate gene readout. This would have the effect of augmenting the normal action of GH to regulate gene readout. We have exciting preliminary data which makes us think this may be a new mechanism for hormone activation of genes. The level of GHBP in the nucleus is regulated, and if a defect in export of the GHBP occurred, this would lead to accumulation of nuclear GHBP and stimulate cell proliferation. This may be important in cancer cell proliferation, since we find nuclear GHBP in cancers.Read moreRead less