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
This project is a biochemical investigation of collagen, which is the principle protein of bone, joints, blood vessels and skin. More than 200 mutations have been identified in the genes for type I collagen that result in Osteogenesis Imperfecta (OI), otherwise known as brittle-bone disease, in children and adults. However, very little is known about how these mutations cause bones to be brittle and why the disease varies so widely in severity. Our experiments are directed towards a better under ....This project is a biochemical investigation of collagen, which is the principle protein of bone, joints, blood vessels and skin. More than 200 mutations have been identified in the genes for type I collagen that result in Osteogenesis Imperfecta (OI), otherwise known as brittle-bone disease, in children and adults. However, very little is known about how these mutations cause bones to be brittle and why the disease varies so widely in severity. Our experiments are directed towards a better understanding of how bone cells respond to the mutant collagen and how these mutations actually result in brittle bones. We know that the majority of OI-causing mutations typically lead to a severe OI because the mutant collagen interferes with normal functioning of the matrix and effectively weakens it. We will examine how the mutant collagen disrupts normal cell function using bone and skin cell lines in which we have added a mutated collagen gene. The mutations we will introduce are the same ones that cause OI in patients. The experiments cannot be carried out with OI cell lines isolated from humans because it is very difficult to identify the mutant collagen in the matrix. Instead we have engineered a marker into the mutant collagen to allow the mutant collagen to be easily tracked. We will then examine how the presence of the mutant collagen affects matrix integrity, turnover and the formation of mutant matrix. In the second part of the study we will make a transgenic mouse that carries a specific collagen mutation. This will allow us to examine the fate of mutant collagen in a whole animal. As with the engineered cells described above, the mutant collagen will be altered to allow easy tracking. Collectively, these experiments will provide valuable information about how the presence mutant collagen disprupts integrity of the extracellular matrix of skin and bone.Read moreRead less
Molecular Mechanisms Of Collagen Matrix Assembly In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,171,996.00
Summary
This project studies the way the specific protein building blocks of tissues interact with each other to form the complicated structural networks necessary for tissue growth, development and function. Specifically, we will study collagens, the main structural proteins of the body. We will determine how they assemble with other proteins to form the complex fibrils or molecular ropes, which provide mechanical strength to tissues and create the environment for cells to grow and develop in tissues s ....This project studies the way the specific protein building blocks of tissues interact with each other to form the complicated structural networks necessary for tissue growth, development and function. Specifically, we will study collagens, the main structural proteins of the body. We will determine how they assemble with other proteins to form the complex fibrils or molecular ropes, which provide mechanical strength to tissues and create the environment for cells to grow and develop in tissues such as bone, skin, cartilage and muscle. We will explore the effect of collagen mutations, that occur in patients with inherited diseases of cartilage and muscle, on these assembly processes. This will provide key information on the disease process, so that in the future new approaches to diagnosis and therapy can be developed. The understanding we gain on the molecular basis of tissue structural assembly from these studies will be of importance for understanding normal tissue growth and development, and for the development of new biomaterials for therapeutic use.Read moreRead less
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
Preclinical Optimisation Of Intrauterine Transplantation Of Fetal Mesenchymal Stem Cells For Osteogenesis Imperfecta.
Funder
National Health and Medical Research Council
Funding Amount
$600,932.00
Summary
Osteogenesis imperfecta is a genetic disorder causing brittle bones and fractures. Currently there is no good treatment. Transplanting stem cells before birth should allow them to build healthy bones early in life. Despite promising effects in animals, stem cell uptake is too low to prevent all fractures and ameliorate pain and deformity. We are studying how to improve the uptake of stem cells given to the fetus and neonate, in order to develop a treatment suitable for eventual use in humans.
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
Functional Contribution Of Fetal Microchimeric Cells In Transgenic Models Of Maternal Tissue Repair In And After Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
Fetal stem cells cross into the mother during pregnancy and persist lifelong in her tissues. To determine whether helpful or harmful, we will study how these cells contribute to healing both after acute injury and in chronic genetic models like brittle-bone disease and muscular dystrophy. This research will inform long-term consequences of pregnancy, important for women's health and longevity, and help develop a promising form of stem cell therapy.
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.