Determining The Genetic Basis Of Skeletal Dysplasias Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$110,068.00
Summary
Osteoporosis is a common condition in Australia, yet treatment options are still limited. Study of rare genetic bone conditions known collectively as skeletal dysplasias have already led to the development of two new osteoporosis drug treatments. My project aims to identify the causative gene for several skeletal dysplasias, and to determine how these genes are involved in the development and maintenance of bone. This knowledge may then translate into new osteoporosis therapies.
MRNA Surveillance In Human Genetic Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$371,275.00
Summary
In about 1/3 of inherited disorders the mutations introduce an abnormal stop signal into the gene so that cells risk producing truncated or erroneous proteins. To prevent this cells have developed control surveillance mechanisms called Nonsense Mediated mRNA Decay (NMD). We have found a new form of NMD and our studies are directed determining how this works in cells, which genes use this pathway, and the consequences of this for human genetic disease.
Dissecting The Role Of Hedgehog Signalling In Chondrogenesis And Skeletal Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,739.00
Summary
There are close to 400 inherited disorders that affect how the skeleton develops, as well as a range of injury and age-related skeletal defects. There is much interest in treating such abnormalities with artificial bone grown outside the body. In order to achieve this aim we must understand all of the processes involved in producing and maintaining bone within the body. We are using both mouse and cell culture models of skeletal development to increase our understanding of these processes.
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
Defining The Genetic Causes Of The Abnormal Vertebral Segmentation Syndrome, Spondylocostal Dysostosis
Funder
National Health and Medical Research Council
Funding Amount
$476,523.00
Summary
There are many birth defects that cause vertebral malformations along the spinal column. These occur as the embryo develops in utero, during the formation of structures known as somites. Somites also form the ribs, muscle, tendons and dermis. We are studying an example of this type of birth defect called spondylocostal dysostosis (SCD). We have shown that mutations in three different genes cause some cases of this inherited disease in humans. These genes are called DLL3, MESP2 and LFNG. However, ....There are many birth defects that cause vertebral malformations along the spinal column. These occur as the embryo develops in utero, during the formation of structures known as somites. Somites also form the ribs, muscle, tendons and dermis. We are studying an example of this type of birth defect called spondylocostal dysostosis (SCD). We have shown that mutations in three different genes cause some cases of this inherited disease in humans. These genes are called DLL3, MESP2 and LFNG. However, 80% of SCD patients do not have a mutation in any of these genes. Thus we need to discover how these other cases occur. This project uses two strategies in parallel. Firstly, we will analyse large families that have a history of SCD, and use this information to find causative gene mutations. However, a significant proportion of cases occur without family history. To find out what genes are involved in these cases is more difficult. We have created a mutant mouse by specifically deleting the DLL3 gene. This mouse has very similar vertebral malformations to SCD. We will compare embryos from normal and mutant mice to find genes that do not operate normally in the mutant. These genes are candidates for causing SCD, and thus we will screen these genes in human patients for mutations. However, simply finding a change in a candidate gene does not necessarily mean that this is the cause of SCD. To prove this, we have developed several tests to determine if the mutation alters the normal function of the protein encoded by the mutated gene. This work will greatly benefit the future genetic assessment of SCD patients. In addition, by studying our mouse model of SCD, we will gain a greater understanding of how DLL3 functions. This knowledge may be useful in developing stem cell-based therapies that involve the production of specific cell types.Read moreRead less
Understanding Human Dysmorphology Through Analysis Of ENU Mutant Mice
Funder
National Health and Medical Research Council
Funding Amount
$602,501.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Rapid Identification And Characterisation Of Genes Involved In Skeletal Development
Funder
National Health and Medical Research Council
Funding Amount
$550,536.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms c ....Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms common to more than one MPS type include mental deterioration, blindness, abdominal organ enlargement and bone growth problems leading to short stature and bone loss. My laboratory has had a long-term interest in developing treatment for MPS and our research led to the clinical implementation of enzyme replacement therapy (ERT) for MPS VI in 2005. While providing the first effective, multi-tissue treatment for MPS, our research showed that several tissues were not responsive to ERT. These are the brain, cartilage and cornea, thus children on ERT regimens will still suffer from mental retardation, arthritis and blindness. With the goal of treating these particular tissues we have developed a new approach to MPS therapy called substrate deprivation therapy (SDT). Instead of adding back the missing enzyme, SDT acts by decreasing gag production which in turn reduces the level of accumulated gag in cells. SDT results in the correction of MPS cells in culture and reduces several key clinical symptoms in the mouse model of MPS IIIA. In this proposal we will extend our research to evaluate the effect of SDT on brain and bone-joint pathology. Evaluation of efficacy will take place in the MPS VII mouse which exhibits both brain and bone disease and in a new model of MPS IVA developed specifically for this study which exhibits a joint pathology unique amongst the MPS disorders.Read moreRead less
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.
The Molecular Mechanisms Of Inherited And Acquired Musculoskeletal Disease
Funder
National Health and Medical Research Council
Funding Amount
$823,008.00
Summary
Diseases of the musculoskeletal system are the second most prevalent medical conditions, and the second leading cause of health care expenditure in Australia. This research program seeks to identify genes causing inherited musculoskeletal disease and osteoarthritis. By identifying these genes, and by understanding the detailed molecular mechanisms of how gene mutations cause these disorders, our research is working towards developing better diagnostic and therapeutic approaches