The Role Of Connexins In Blood Pressure Regulation: Use Of A Conditional Gene Expression System
Funder
National Health and Medical Research Council
Funding Amount
$583,767.00
Summary
Cell coupling through gap junctions is said to play an important role in regulating blood flow and blood pressure. However data obtained from mice, in which specific gap junctions are deleted, may be compromised by compensatory changes in other junctions. We have validated a new method for rapidly and reversibly altering gap junctions in adult mice with oral sugar. This technique will enable us to directly determine whether interference with cell coupling affects blood flow and blood pressure.
The Role Of Connexin40 In The Pathogenesis Of Atrial Fibrillation Probed By Targeted In Vivo Gene Transfer
Funder
National Health and Medical Research Council
Funding Amount
$529,015.00
Summary
Atrial fibrillation (AF) is a fast and irregular heart rhythm that can predispose sufferers to heart failure and stroke. AF occurs as the result of abnormal electrical conduction in the upper heart chambers. We have found that a protein called Cx40 causes abnormal conduction in heart cells when grown in culture. The aim of this research is to see if AF occurs when Cx40 is increased and prevented when Cx40 is decreased in an AF animal model, potentially defining Cx40 as new therapeutic target.
Myoendothelial Gap Junctions: Their Composition And Role In Vasodilator Responses Attributed To EDHF
Funder
National Health and Medical Research Council
Funding Amount
$282,750.00
Summary
Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important ....Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important as a source of relaxing factors, while under hypertensive conditions, the balance is shifted in favour of the release of constricting factors. Thus, restoration of the vasodilatory function of the endothelium is seen as an important new therapeutic target in the treatment of vascular disorders. Present data suggests that the action of one of the major endothelial derived vasodilatory factors, the so-called endothelium-derived hyperpolarizing factor, EDHF, requires the presence of particular structures within the vascular wall, but little is known about the molecules of which they are comprised. We have identified two unique situations, during development and during hypertension, when these structures are present in vessels in which they are absent in normal adults. We will use gene microarrays to identify the specific molecules involved in these structures and use physiological studies to test the role of these proteins and structures in vasodilatory responses. The results of these studies may identify new targets for therapeutic intervention to restore the action of EDHF in hypertension.Read moreRead less
RNA Interference And Retigabine Therapy Protect Against Hereditary Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$370,522.00
Summary
The preservation of hearing function is central to the treatment of individuals who are genetically predisposed to hearing loss. At present only synthetic hearing aids and cochlear implants can provide functional improvement, albeit sub-optimal. The studies described here will seek to prevent hearing loss by reducing the damaging effects of defective genes. Gene therapies that reduce the effect of these defective genes and a drug that enhances the activity of functional genes will be developed.
Genomic Characterisation Of Asbestos Related Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$88,099.00
Summary
Lung cancer causes more deaths in Australia than any other cancer. Smoking is the main cause, but people exposed to asbestos are also at risk, and it can be difficult to know whether a case is due to tobacco, asbestos or both. We will study lung cancer genes in people with asbestos exposure to find whether asbestos lung cancer has a specific pattern of abnormal genes (signature). If so, this could help people entitled to compensation, and also point to new treatments for asbestos lung cancer
Retrotransposon Regulation Of The Human Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$231,937.00
Summary
Complete sequencing of the human genome has revealed the positions of approximately 20,000 genes. In addition, nearly 50% of the human genome is comprised of repetitive sequences previously thought of as junk DNA. Numerous studies are now finding that this DNA actually has a variety of important functions, particularly in the control of gene activity. This project will examine the relationships between gene expression and nearby repetitive sequences during the innate immune response in humans.
The Role Of UPF3B And Nonsense Mediated MRNA Decay Surveillance In The Pathology Of Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$789,954.00
Summary
Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundam ....Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundamental importance.Read moreRead less
Integrating Immunity And Genetics In Follicular Lymphoma To Establish A Prognostic Score Fit For The Modern Era
Funder
National Health and Medical Research Council
Funding Amount
$1,377,174.00
Summary
Follicular lymphoma (FL) is divided into early and advanced stages. Early stage FL is frequently cured, but there is no way to identify who will be cured and who won't. By contrast advanced stage FL is incurable. Our unique access to well-annotated clinical trial and population based cohorts allows us to perform a detailed biological comparison of early and advanced FL, to gain a deeper understanding of the impediments to eradicating the disease, and to predict outcome to conventional therapy.
Development Of Therapeutically Useful Human Artificial Chromosomes For Gene Delivery And Optimal Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$496,986.00
Summary
Gene therapy is an exciting new form of treatment for genetic disorders aimed at providing long-term correction of the problems at source - namely the affected gene. The biggest technical hurdle facing gene therapy is to be able to deliver the therapeutic genes efficiently and safely into patient cells. Many gene therapy protocols are currently being trialled clinically. These protocols, based mostly on the use of attenuated viruses to deliver the genes, carry potential risks to the patients in ....Gene therapy is an exciting new form of treatment for genetic disorders aimed at providing long-term correction of the problems at source - namely the affected gene. The biggest technical hurdle facing gene therapy is to be able to deliver the therapeutic genes efficiently and safely into patient cells. Many gene therapy protocols are currently being trialled clinically. These protocols, based mostly on the use of attenuated viruses to deliver the genes, carry potential risks to the patients in terms of infection, immune response, and germline modification. We have developed the first stage of a new technology for gene delivery that does not require the use of viruses. This technology is based on the generation of human artificial chromosomes, which are smaller versions of the naturally occurring chromosomes that carry all the genes inside our cells. Safety in these artificial chromosomes comes from the use of entirely human materials for their engineering. These artificial chromosomes also have other advantages over the viral approaches, including allowing large genes to be carried, and providing a permanent cure in a single treatment. We have already successfully constructed, published, and patented a number of first-generation human artificial chromosomes. The current project aims to complete the next proof-of-concept milestone towards the further development of this technology. Specifically, we propose to demonstrate the ability of the artificial chromosomes to carry genes and provide sustainable expression of these genes in cells and in animal models. Success in this study will allow the technology to proceed rapidly into commercialisation and clinical trial as a new improved tool for gene delivery and gene therapy.Read moreRead less