Gastric Counter-regulation Of Hypoglycaemia: Studies In Health And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$357,193.00
Summary
Insulin injections are often needed to treat diabetes, but they can cause low blood sugar levels (hypoglycaemia), which are usually distressing, and sometimes fatal. The stomach is important in regulating blood sugar; in response to hypoglycaemia, it empties food much more rapidly, allowing carbohydrate to be absorbed faster to normalise blood sugar levels. The proposed studies will explore this important area, in order to develop better ways of preventing and treating hypoglycaemia.
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less
The Regulation Of Aromatase In The Context Of Obesity And Postmenopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$436,601.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen formation results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen formation is regulated with the goal of developing breast-specific inhibitors of oestrogen formation to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.
Correction Of Diabetes In An Autoimmune Model Using Insulin-secreting Liver Cells.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology ....Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology is to deliver the insulin gene directly to a patient's own liver cells which would regulate insulin secretion in response to glucose and other substances that stimulate insulin secretion, controlling blood glucose without the need for immunosuppression. To accomplish this it must be possible to deliver the insulin gene efficiently to primary liver cells (cells derived from an animal's or human's body). Results from our laboratory using a non-pathogenic viral delivery system indicate that we can reverse diabetes in chemically induced diabetic rats by expression of insulin and a beta cell transcription factor NeuroD. The aim of this study is to repeat this in an auto-immune model of diabetes the nonobese diabetic mouse, which mimicks very closely the development of diabetes in humans. We will determine if we can reverse diabetes in these animals and determine if their response to glucose is normal over an extended period of time, with no attack by the factors of the immune system that stimulate the development of diabetes in man. The results from this research proposal should result in the delivery of the insulin gene to large numbers of primary liver cells that will then synthesise, store and secrete insulin in response to glucose. These cells would control blood glucose levels in patients without the need for immunosuppression.Read moreRead less
Intervening In The Natural History Of Type 1 Diabetes: An Integrated Approach
Funder
National Health and Medical Research Council
Funding Amount
$9,466,000.00
Summary
This Program brings together four of Australia’s top type 1 diabetes clinical and lab-based research teams. The program has three intersecting themes. The first theme, pathogenesis, focuses on early life and understanding why type 1 diabetes develops. The second theme, prevention, seeks to identifying new drugs to stop the disease from occurring. The third theme, treatment, aims to improve therapies to replace the cells that are destroyed during the disease process.
Transforming Mealtime Insulin Dosing Using An Innovative New Bolusing Calculator To Optimise Glycaemic Control In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
People with type 1 diabetes require life-long insulin injections to maintain their blood glucose levels in the optimal range. Mealtime dose estimations based solely on carbohydrate have limited efficacy as they fail to take fat and protein into account. The aim of this project is to develop an evidence-based insulin bolusing calculator integrated into a smartphone app to enhance blood glucose control and reduce the daily burden of disease and the risk of life-threatening complications.
Free-Living Closed-Loop Insulin Delivery For Patients With Type 1 Diabetes: A Long-term Multi-centre Randomized Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$1,041,986.00
Summary
Closed loop technology for automating the delivery of insulin to patients with Type 1 diabetes has the potential to improve the lives of many with the disease. Though early prototypes are currently under evaluation in small studies, no studies have yet to date applied the technology in a large scale randomised trial. We propose to undertake such a study in order to demonstrate the utility of this technology and facilitate its eventual routine and widespread use in the community in the future.
Type 1 Diabetes And The Metabolic Syndrome: Defining This Modern-day Phenotype, And Exploring The Effects Of Exercise On Glycaemic Control And Both Traditional And Novel Diabetes Complications
Funder
National Health and Medical Research Council
Funding Amount
$122,714.00
Summary
This research aims to define trends in the prevalence of, and complications associated with, metabolic syndrome in adults with type 1 diabetes, using the Australian National Diabetes Information Audit and Benchmarking Initiative (ANDIAB). Subsequently, a randomised controlled trial will examine the effect of exercise on glycaemic control and diabetes complications risk profiles in this group. These studies will thus address disease profiles and a potential beneficial clinical intervention.
Understanding The Early-life Pathways For Adult Type 2 Diabetes Using Existing Data From Seven Cohorts Of The International Childhood Cardiovascular Cohort (i3C) Consortium
Funder
National Health and Medical Research Council
Funding Amount
$336,419.00
Summary
This project will allow us to determine the role that child factors play in the development of diabetes. We will do this using information that has been collected from individuals at several ages extending from childhood to adulthood, somewhat like the “Up” TV series. The project’s findings could lead to improvements in the way we identify people who are at risk of having adult diabetes. By doing so, we could begin programs to stop the young from being struck down by this debilitating disease.