ER Stress-Unfolded Protein Response A Critical Metabolic Pathway For Airway Remodelling In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$789,475.00
Summary
Airway remodelling in asthma is associated with poor clinical outcomes and is not prevented by current treatments. We have found endoplasmic reticulum stress (ERS) and associated unfolded protein response (UPR), a crucial process involve in cellular protein folding, play a key role in airway remodelling in asthma. This study will investigate whether inhibition of ERS prevents goblet cell metaplasia, mucus hypersecretion and fibrosis and can be used as a therapeutic strategy for severe asthma.
The Role Of Endoplasmic Reticulum (ER) Stress In Pancreatic Beta-cell Dysfunction.
Funder
National Health and Medical Research Council
Funding Amount
$85,775.00
Summary
Diabetes results from pancreatic ß-cell failure which is characterised by insulin secretory defects and ß-cell destruction. This is mediated by inflammatory cytokines in type 1 diabetes and by high levels of fat in type 2 diabetes. The mechanisms by which ß-cells fail remain to be clarified but they are important considering the current epidemic of diabetes in Australia. This project will enhance our understanding of ß-cell failure and may provide therapeutic targets for diabetes treatment.
Despite the high mortality associated with colon cancer only limited therapy options are available to treat these cancers. Here we propose a new strategy for inhibiting colon cancers driven by a specific type of mutations. Our preliminary data show that loss of DNA encoding a tumor suppressor gene creates a unique vulnerability in colon cancers. The aim of this proposal is to exploit this vulnerability as a strategy for combating colon cancer.
The proposal focuses on a novel angle explaining how pancreatic beta cells normally match their insulin synthesis, storage and secretion in response to an enhanced demand as occurs during obesity, and how this fails in the progression to Type 2 diabetes. In particular we will expand our discovery that glucose rapidly enhances the synthesis of a novel factor regulating gene transcription. This will generate basic knowledge that will potentially help design of novel therapies for Type 2 diabetes.
Collagen II Mutations And The Unfolded Protein Response In Inherited Cartilage Disease
Funder
National Health and Medical Research Council
Funding Amount
$92,314.00
Summary
In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. My studies will determine the role of cell stress in a clinically important group of diseases, caused by cartilage collagen mutations, that result in abnormal development of the skeleton. These studies will define the mechanisms of how cell stress causes these disorders; knowledge that will underpin the development of new therapeutic strategies
The Obesity Prone Oocyte- Causes, Consequences, Treatments
Funder
National Health and Medical Research Council
Funding Amount
$516,159.00
Summary
Obesity is perpetuated from mothers to offspring, in part due to changes in the oocyte (egg) that affect embryo growth. We have discovered that obesity causes changes in the mitochondria (the energy producers) of the egg. We hypothesise this causes long-lasting changes to embryo metabolism and will test, in mice, novel treatments to reverse the detrimental effects. The project will show how obesity affects embryo metabolism and growth, and determine whether defects can be prevented by drugs or l ....Obesity is perpetuated from mothers to offspring, in part due to changes in the oocyte (egg) that affect embryo growth. We have discovered that obesity causes changes in the mitochondria (the energy producers) of the egg. We hypothesise this causes long-lasting changes to embryo metabolism and will test, in mice, novel treatments to reverse the detrimental effects. The project will show how obesity affects embryo metabolism and growth, and determine whether defects can be prevented by drugs or lifestyle changes.Read moreRead less
N-glycosylation In Health And Disease: A Key Role For Ost3p And Ost6p In Regulation Of Substrate Specificity.
Funder
National Health and Medical Research Council
Funding Amount
$523,084.00
Summary
Protein glycosylation is the addition of complex sugar chains to specific proteins. Proteins on the surface of cells are often glycosylated, and this is important for controlling the interactions between cells that occur in development, cancer and infection. Glycosylation can be regulated, and our research will characterize the mechanisms of this regulation. This will help us understand exactly how glycosylation is important in cancer and development.
ASSESSMENT OF ENDOPLASMIC RETICULUM STRESS AND MUTATIONS IN MUCIN OLIGOMERIZATION DOMAINS IN ULCERATIVE COLITIS
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Ulcerative colitis affects 0.2% of Australians causing chronic or recurrent health morbidity and affecting employment. In severe cases it is life threatening. Its pathogenesis remains poorly understood. We have exciting and novel preliminary data from humans and informed by our unique animal models that make us propose that the disease is caused by Endoplasmic Reticulum Stress due to misfolding of mucin. We have designed fully powered prospective clinical and lab studies to test this hypothesis.
The Unfolded Protein Response In Inherited Musculoskeletal Disease - Mechanisms And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$643,607.00
Summary
In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of debilitating inherited bone and cartilage diseases caused by collagen mutations. Our studies will explore the mechanisms of how this stress causes the disease, but importantly will translate these findings by testing a new therapeutic strategy strengthen bones in brittle bone disea ....In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of debilitating inherited bone and cartilage diseases caused by collagen mutations. Our studies will explore the mechanisms of how this stress causes the disease, but importantly will translate these findings by testing a new therapeutic strategy strengthen bones in brittle bone disease.Read moreRead less