The Unfolded Protein Stress Response In Inherited Skeletal Disease: Mechanism And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
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 skeletal diseases caused by collagen mutations. We will also test how we can use small chemicals to alleviate the damage done to the cells by the misfolded proteins, in the hope that this approach will provide new therapeutic strategies for these disorders.
Skeletal disease is a major problem for children with mucopolysaccharidoses (MPS). Patients suffer from early onset osteoporosis and osteoarthritis, severely affecting their quality of life. We will evaluate a lentiviral gene therapy vector developed in-house for its capacity to transduce bone, cartilage, synovial and ligament cells in a mouse model of MPS VI. Our goal is to generate high level, sustained expression of the deficient MPS enzyme and alter the course of skeletal disease in MPS.
Deregulation Of DNA Hydroxymethylases Tet1/ Tet2 Compromises Skeletal Integrity During Ageing And Bone Disease
Funder
National Health and Medical Research Council
Funding Amount
$850,229.00
Summary
Epigenetic modifications of DNA and associated proteins regulate gene expression. A greater understanding of the molecular pathways and associated epigenetic changes that regulate bone cell commitment under normal and pathological conditions will help enhance our ability to diagnose and treat disorders/ diseases that effect skeletal tissues through the pharmacological manipulation of epigenetic modifiers and their gene targets.
Disruption And Restoration Of Motor Control In Musculoskeletal Pathology: Implications For Physiotherapy Management
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
The way in which the nervous system controls muscles and movement may play a role in the development and progression of common musculoskeletal conditions. One of these conditions is patellofemoral pain syndrome which is associated with pain around the knee cap. This condition may result from an imbalance in the activity of the thigh muscles that control movement of the knee cap as the knee bends and straightens. This imbalance is due in part to problems with the control of the muscles by the ner ....The way in which the nervous system controls muscles and movement may play a role in the development and progression of common musculoskeletal conditions. One of these conditions is patellofemoral pain syndrome which is associated with pain around the knee cap. This condition may result from an imbalance in the activity of the thigh muscles that control movement of the knee cap as the knee bends and straightens. This imbalance is due in part to problems with the control of the muscles by the nervous system. Our previous studies have shown that physiotherapy treatment aimed at restoration of the control of the knee muscles results in clinical improvement of the condition. The first part of this project will investigate possible reasons for this muscle imbalance including the effects of pain, swelling and muscle fatigue. Understanding the reasons for the imbalance in muscle activity will help direct and refine more appropriate treatment strategies for this and other musculoskeletal conditions. The second part will assess whether a specific physiotherapy muscle training program for the thigh muscles is more effective in correcting the muscle imbalance than a more generalised thigh strengthening exercise program. The results will help us to better understand why the condition occurs and how we can best assess and treat the problem.Read moreRead less
Common Pathways Influencing Osteoporosis And Atherosclerosis Clinical Risk
Funder
National Health and Medical Research Council
Funding Amount
$443,090.00
Summary
It is recognised there are strong inherited effects on bone density and bone turnover as well as cardiovascular markers like serum cholesterol and arterial function. The study will examine the relationship between osteoporosis and atherosclerosis risk using the powerful twin model and two established large twin cohorts in Sydney and Melbourne. The work may lead to better prediction of common risk factors for these two important conditions.
Defining Treatment Targets To Optimise The Management Of Early Midfoot Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
Midfoot osteoarthritis (OA) is a common cause of foot pain and responsible for significant pain and disability. This project will investigate the early structural and functional changes in the midfoot joints and determine the relationships between foot joint loading, structural changes, symptoms and functional impairment. This will identify modifiable factors involved in midfoot OA and define treatment targets to inform the development of effective interventions.
Mutation Analysis Of Novel Candidate Genes For X-linked Charcot Marie Tooth (CMTX3) Neuropathy.
Funder
National Health and Medical Research Council
Funding Amount
$191,434.00
Summary
Our goal is to explore how peripheral nerves degenerate by identifying the gene mutation causing an X linked form of Charcot Marie Tooth neuropathy (CMTX3). Using bioinformatic resources and state of the art gene mutation scanning we will complete characterisation and systematic screening of candidate genes and novel transcripts in the region. Discovery of this gene will provide a means to determine mechanisms causing axonal degeneration and lead to targeted therapeutic treatment strategies.
The Role Of Huntingtin Misfolding And Oligomerization In Huntingtons Disease
Funder
National Health and Medical Research Council
Funding Amount
$474,329.00
Summary
Mutations in the huntingtin gene cause Huntington's disease by making the gene product aggregate together into non-normal and different sized polymers. However, it is not understood how this process causes cells to die, largely because we don't understand how the abnormal forms accumulate in cells over time. We will examine where in cells the abnormal shapes accumulate and how they cause toxicity. This research will identify critically-needed therapeutic targets against Huntington's disease.
Prevention Of Musculoskeletal Disorders And Cardiovascular Disease – Improving The Evidence-base For Primary Health Care
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
Bone and joint problems and cardiovascular disease (CVD) are common in general practice. My research will provide high quality information on how to prevent these conditions in general practice. For example, the studies test: how assessments of people’s risk of a disease might be used to improve their lifestyle behaviours; a new way for GPs to identify patients at high risk of CVD and ways to prevent osteoarthritis progression and to improve bone health in young women and children.