A Study Of The Origins Of Macrophages In Healthy And Atherosclerotic Vasculature Focusing On A Novel Population Of Resident Adventitial Macrophage Progenitor Cells (AMPCs)
Funder
National Health and Medical Research Council
Funding Amount
$465,345.00
Summary
White blood cells (macrophages) play a key role in the development of atherosclerosis, the underlying cause of most heart attacks and strokes. We have made new discoveries to show that there are stem (progenitor) cells for macrophages that exist within the outer lining of blood vessels. This project will study whether these local progenitor cells, called AMPCs, are a source of macrophages in atherosclerosis and in turn could lead to new treatment approaches for cardiovascular disease.
The Role Of Tissue Factor Pathway Inhibitor (TFPI) In The Pathogenesis Of Lymphatic Malformations
Funder
National Health and Medical Research Council
Funding Amount
$87,198.00
Summary
Lymphatic malformations or cystic hygomas are growths of abnormal blood vessels called 'lymphatic vessels'. They are present at birth, commonly affect the head and neck, and can cause lifelong problems due to growth in size and frequent infections. Surgical treatment does not offer a cure, and problems often persist lifelong. The finding that blood clots are continuously forming and breaking down in these growths may provide a clue to relieving symptoms and understanding the cause of this condit ....Lymphatic malformations or cystic hygomas are growths of abnormal blood vessels called 'lymphatic vessels'. They are present at birth, commonly affect the head and neck, and can cause lifelong problems due to growth in size and frequent infections. Surgical treatment does not offer a cure, and problems often persist lifelong. The finding that blood clots are continuously forming and breaking down in these growths may provide a clue to relieving symptoms and understanding the cause of this condition.Read moreRead less
A Critical New Signaling Axis In Lymphatic Vascular Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$700,784.00
Summary
The lymphatic vasculature is a crucial part of our vascular system required for tissue fluid drainage and maintenance of fluid homeostasis. Lymphatic vessels play major roles in vascular pathologies and in the spread of solid tumours during cancer progression. We have discovered a new molecular regulator controlling the formation of lymphatic vessels. This project will determine the signalling pathway employed by this new regulator and potential for future therapeutic applications.
Coupling The Mechanical, Signalling And Transcriptional Mechanisms That Initiate Pathogenesis Of Cerebral Cavernous Malformation
Funder
National Health and Medical Research Council
Funding Amount
$1,228,364.00
Summary
Cerebral cavernous malformations (CCMs) are thin walled, vascular malformations in the brain found in 1/200-250 individuals. They can cause migraine, neurological deficits or stroke. This disease can be inherited due to damaging mutations in any of three CCM genes. The project will investigate the molecular control of CCM pathogenesis in animal models. We aim to uncover the molecular cause of these vascular malformations and in doing so identify new therapeutic strategies.
Defining The Role Of VEGF And Vascular Formation In Craniofacial Development
Funder
National Health and Medical Research Council
Funding Amount
$636,417.00
Summary
Aberrant neural crest cell development gives rise to common congenital malformations such as cleft lip and/or palate and cardiac outflow tract defects that effect over 1% of all births. As the aetiology of these disorders are largely unknown it is critical to understand the cell and molecular mechanisms coordinating NCC development such that alternative therapies may be devised to target the underlying pathological defects and to provide definitive diagnostic / prognostic tools.
Defining The Role Of The Ubiquitin Protein Ligase Nedd4 In Vascular Development.
Funder
National Health and Medical Research Council
Funding Amount
$702,166.00
Summary
Blood and lymphatic vessels are vital components of the cardiovascular system. Abnormalities in the growth and development of these vessels are associated with human disorders including cancer and cardiovascular disease. The focus of this application is to characterise the role of the ubiquitin protein ligase Nedd4 in vascular development, with the aim of identifying targets to which novel therapeutics for the treatment of blood and lymphatic vascular diseases could be generated.
Modulation Of Vegfc/Vegfr3 Signaling At The Extracellular Matrix During Embryonic Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$570,928.00
Summary
Lymphatic vessels play important roles in vascular diseases and cancer. However, we are yet to understand how they form during development and disease. We recently identified the gene CCBE1, essential for the formation of lymphatic vessels and responsible for lymphatic dysplasia in humans. This study aims to understand the molecular pathway in which CCBE1 acts. This work aims to characterize new molecular pathways in lymphatic vessels in order to identify new therapeutic targets in lymphatic dis ....Lymphatic vessels play important roles in vascular diseases and cancer. However, we are yet to understand how they form during development and disease. We recently identified the gene CCBE1, essential for the formation of lymphatic vessels and responsible for lymphatic dysplasia in humans. This study aims to understand the molecular pathway in which CCBE1 acts. This work aims to characterize new molecular pathways in lymphatic vessels in order to identify new therapeutic targets in lymphatic disease and cancer.Read moreRead less
Regulation Of VEGFR Trafficking And Signal Transduction By The Ubiquitin Ligase Nedd4
Funder
National Health and Medical Research Council
Funding Amount
$388,347.00
Summary
Our recent work has discovered that the Nedd4 gene is crucial for the growth and development of blood vessels and lymphatic vessels. Our data suggest that Nedd4 controls vessel growth by regulating the levels and signalling activity of the key vascular growth factor receptors VEGFR-2 and VEGFR-3. The goals of this proposal are to define precisely how Nedd4-1 regulates the activity of these receptors and how VEGFR signalling could be better targeted to treat vascular disorders.
The Role Of Crim1, A Novel TGFb Superfamily Modulator, In Early Vertebrate Patterning, Vascular And Renal Development.
Funder
National Health and Medical Research Council
Funding Amount
$501,300.00
Summary
The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be dele ....The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be deleterious, with their overexpression leading to conditions such as renal fibrosis and cataract. The activity of these growth factors is regulated by many other proteins, including protein antagonists which bind and inactivate them. It is therefore possible that by understanding these antagonists, we can find new ways of altering TGF beta superfamily activity. We have previously identified a novel protein, Crim1, which we have now shown can bind to TGF superfamily members and can reduce their secretion. We believe that Crim1 plays a role in the patterning of the central nervous system, the development of the blood vessels and the kidneys by regulating the TGFbeta superfamily. In this grant we will be investigating what the effect of disruption to Crim1 is on these organ systems and working out which members of the TGFbeta superfamily it is affecting to cause these effects. To do this, we will knock out the gene in zebrafish and characterise the defects found in a mouse line in which the gene has been disrupted. This may be important in developing new ways of activating or inactiviating these growth factors in a number of clinical conditions.Read moreRead less