Molecular Mechanisms For The Cell-type Specific Regulation Of The Tissue-type Plasminogen Activator Gene
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will ....Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will address the mechanisms underlying the cell-type specific regulation of the t-PA gene. Endothelial cells, fibroblasts and neuronal cell cultures will be used to study the regulation of t-PA expression. Information gained will not only add to the understanding of the broader field of gene regulation, but may also provide clues to manipulate the expression of the t-PA gene in different cells.Read moreRead less
The function of menin in mammalian development. This project aims to determine the role of a ubiquitous transcriptional co-regulator, menin, in mammalian development. Mice that lack menin through targeted deletion of the gene die during embryogenesis, but the cause is unknown, although is likely to be due to the abnormal expression of genes usually regulated by this factor. We will determine which genes are inappropriately expressed and responsible for the accompanying developmental defects. Thi ....The function of menin in mammalian development. This project aims to determine the role of a ubiquitous transcriptional co-regulator, menin, in mammalian development. Mice that lack menin through targeted deletion of the gene die during embryogenesis, but the cause is unknown, although is likely to be due to the abnormal expression of genes usually regulated by this factor. We will determine which genes are inappropriately expressed and responsible for the accompanying developmental defects. This knowledge will help us understand the process of development in mammals, including birth defects in humans.Read moreRead less
Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contrib ....Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contribute to our basic knowledge of these processes, provide invaluable information about the specific genes and proteins involved, and provide direct information about the therapeutic potential of specific drugs or inhibitors designed to target this oxygen response in human disease.Read moreRead less
Gene regulatory networks in heart development. In humans, structural and functional malformations of the heart are very common and are associated with a high economic and emotional burden. In this project, we will study how genetic networks initiate and control heart development at a molecular level. We will establish and employ state-of-the-art technologies and bioinformatics tools to explore the function of cardiac regulatory genes in detail. Our work will contribute both to discover new cardi ....Gene regulatory networks in heart development. In humans, structural and functional malformations of the heart are very common and are associated with a high economic and emotional burden. In this project, we will study how genetic networks initiate and control heart development at a molecular level. We will establish and employ state-of-the-art technologies and bioinformatics tools to explore the function of cardiac regulatory genes in detail. Our work will contribute both to discover new cardiac pathways for a better understanding of heart formation and disease, and to develop advanced techniques that will contribute to strengthen Australian basic and strategic research.Read moreRead less
New functions for bioactive flavonoids in plants and mammals. We have discovered natural products with biological activity in plants and mammals. These molecules affect plant shape and development and the process of mammalian blood vessel formation. We seek to understand how these molecules work. More understanding is required before one can begin to utilise these molecules for possible beneficial agriculture or human health outcomes. Plant shape influences such things as yield or more drought-r ....New functions for bioactive flavonoids in plants and mammals. We have discovered natural products with biological activity in plants and mammals. These molecules affect plant shape and development and the process of mammalian blood vessel formation. We seek to understand how these molecules work. More understanding is required before one can begin to utilise these molecules for possible beneficial agriculture or human health outcomes. Plant shape influences such things as yield or more drought-resilient root systems. Importantly, we have discovered specific molecules that either promote or inhibit blood vessel formation. A better understanding of how these molecules work could lead to novel treatments for cancer or cardiovascular disease.Read moreRead less
Pre-clinical evaluation of snake venom proteins with therapeutic potential. Australia harbors some of the most toxic snakes in the world. Their venoms contain a range of substances that are designed to rapidly immobilize and kill their prey. These include agents that lead to enhanced blood clotting; excess bleeding. We have isolated and characterized a large number of the components involved over the last several years. The aim here is to carry out pre-clinical trials in animal models to test th ....Pre-clinical evaluation of snake venom proteins with therapeutic potential. Australia harbors some of the most toxic snakes in the world. Their venoms contain a range of substances that are designed to rapidly immobilize and kill their prey. These include agents that lead to enhanced blood clotting; excess bleeding. We have isolated and characterized a large number of the components involved over the last several years. The aim here is to carry out pre-clinical trials in animal models to test the efficacy of three proteins as anti-bleeding agents and investigate several other novel components. The ultimate outcome will be the development of novel drugs that will have application in the treatment of human disorders. Read moreRead less
Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We wi ....Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We will attempt to alter the balance of stem cell production by enforced p38 expression, and take microarray and proteomics approaches to define stem cell pathways.Read moreRead less
Regulation of mammalian heart development by transcription factors FHL2, GATA-4 & FOG-2. FHL2 is involved in many biological processes including intracellular signaling and gene transcription. GATA and FOG proteins are critical for the development of diverse tissues, including the heart. Knowledge gained in this project will advance our understanding of many cellular processes, including heart development, and will contribute to our knowledge in Biology, Zoology and Veterinary Science. More spe ....Regulation of mammalian heart development by transcription factors FHL2, GATA-4 & FOG-2. FHL2 is involved in many biological processes including intracellular signaling and gene transcription. GATA and FOG proteins are critical for the development of diverse tissues, including the heart. Knowledge gained in this project will advance our understanding of many cellular processes, including heart development, and will contribute to our knowledge in Biology, Zoology and Veterinary Science. More specifically, it will contribute to Stem Cell research, a 'hot' area in the biotechnology industry, particularly towards building a strong base of expertise, skills and technological capability in this new field, and may even lead to the development of a commercial product e.g. a heart muscle cell-coated biomaterial to aid failing heart.Read moreRead less
In Vivo And In Vitro Studies Of The Human -308 TNF Promoter Polymorphism.
Funder
National Health and Medical Research Council
Funding Amount
$232,131.00
Summary
The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarif ....The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarify some of these questions, we will generate genetically modified mice that have either of the two genetic forms of the human TNF promoter. These mice will be compared in two models of associated disease, murine Lupus and cerebral malaria. We will also characterise the interactions of TPF1 with other components of the TNF control region. An understanding of the role of TPF1 in controlling TNF expression and an appreciation of the cell types that are able to express the phenotype, will allow the development of more subtle, cell specific strategies to modulate the activity of TNF without completely abolishing expression and may lead to better preventative and therapeutic strategies.Read moreRead less