Skeletal Disease In A Dish: Using Novel In Vitro Disease Models Produced From Patient Induced Pluripotent Stem Cells To Reveal Pathogenic Mechanisms And Explore Treatments For Genetic Skeletal Disorders
Funder
National Health and Medical Research Council
Funding Amount
$808,551.00
Summary
Inherited skeletal disorders are a significant disease burden. Many gene mutations have been defined but we only have limited understanding about how they cause the disease. We will use patient skin cells and a new in vitro cell reprogramming technology to induce them to form cartilage and bone cells to produce mutation-specific “disease in a dish” models. These models will allow us to answer questions about how specific mutations cause disease and test novel drug therapies
The Effect Of Hypochlorite On The Toxicity And Clearance Of The Alzheimer’s Disease-associated Amyloid Beta Peptide
Funder
National Health and Medical Research Council
Funding Amount
$461,496.00
Summary
Alzheimer’s disease (AD) is the leading cause of dementia worldwide and a growing burden on our aging society. Recent studies support the idea that in AD a deleterious relationship exists between inflammation in the brain and the accumulation of amyloid beta (A?), a peptide with toxic properties. This proposal aims to examine the details of this relationship with a focus on the toxicity and clearance of A? when it is modified by hypochlortie, a chemical that is generated during inflammation.
Investigating The Interaction Of Precursor Inner Membrane Proteins With Translocase Components
Funder
National Health and Medical Research Council
Funding Amount
$585,274.00
Summary
Proteins are synthesised on ribosomes located in the cellular plasm, and then moved to their site of action by specialised transport systems. Import of proteins to the mitochondria involves translocase pores, which come equipped with receptors and chaperones. We are investigating the targeting and transfer of newly synthesised proteins of the MCF carrier family from the ribosomal machinery to the inner mitochondrial membrane, focusing on interaction with chaperones in the intermembrane space.
Targeting Small Heat Shock Proteins In Diseases Associated With Alpha-synuclein Aggregation
Funder
National Health and Medical Research Council
Summary
This research will provide fundamental insight into processes that control the onset and progression of neurological diseases such as Parkinson’s disease, and may lead to the development of novel drugs to treat these disorders. The work will increase Australia's international research standing and provide high-quality multi-disciplinary training to research students.
Understanding The Interplay Between ER Stress And Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$560,918.00
Summary
Chronic inflammatory diseases in the gut and lung affect hundreds of thousands of Australians. We have identified how inflammation causes a type of stress resulting in abnormal protein synthesis in the cells which make the barrier to microbes. Following an infection this process might be the trigger for chronic unresolving inflammatory disease. The further understanding of this process we seek in this project is likely to lead new approaches to treat common inflammatory diseases.
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
Role Of Hsp40 And Hsp70 In Huntingtin Misfolding, Oligomerization And Inclusion Assembly
Funder
National Health and Medical Research Council
Funding Amount
$590,103.00
Summary
Huntington disease results from a mutation that causes the Htt protein to become abnormally sticky and form toxic clusters in neurons. Cells have natural defences to clustering with proteins called chaperones, which are exciting therapeutic targets. This project will examine how chaperones defend against toxic Htt clustering with cutting-edge imaging technologies. The knowledge gained will aid in designing therapeutic strategies that stimulate the defence processes and suppress the clusters.
Developing Novel Molecules That Target Hormone Receptors As An Alternative Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$459,867.00
Summary
A promising class of cancer drugs target heat shock protein 90 (Hsp90) and prevent Hsp90 from maintaining its ~100 proteins involved in cell growth. However, all current Hsp90 chemotherapeutics non-selectively target proteins maintained by Hsp90, and induce a cell rescue mechanism involving Hsp70. We describe the development of a novel molecule that will selectively control cell growth and prevent cell rescue via a unique Hsp90 regulated mechanism.
Understanding Age-related Protein Aggregation. The Mechanism Of Cataract And Its Prevention
Funder
National Health and Medical Research Council
Funding Amount
$709,333.00
Summary
Cataract arises from clouding of the eye lens due to the aggregation of crystallin proteins whose high concentration and close packing facilitate lens transparency. This proposal will investigate crystallin structure and interactions to understand the reasons for cataract formation and its prevention via the design of aggregation inhibitors. The results will facilitate the development of drugs to prevent cataract and other related protein aggregation diseases, e.g. Alzheimer’s and Parkinson’s.
Disrupting Mucin-mucin Interactions To Treat Respiratory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$480,531.00
Summary
Diseases like asthma, emphysema and cystic fibrosis all feature the overproduction of mucus in the lungs that make it very difficult for patients to breathe and increases their susceptibility to infections. Few therapies are available for thinning this mucus, which is made thick by a network of linkages between proteins. We are studying these linkages and developing methods to break them up. This research could yield new mucus-thinning drugs to treat lung diseases.