The Mechanism Of Ccbe1 Function During Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$502,437.00
Summary
Tumours induce the regional growth of lymphatic vessels (in a process termed lymphangiogenesis) and then spread (a process termed metastasis) via lymphatic vessels and lymph nodes. Inhibiting lymphangiogenesis can inhibit metastasis. We have identified a gene called ccbe1 that is essential for lymphangiogenesis during development. We aim to understand how this potential therapeutic target functions at the molecular level during lymphangiogenesis.
We have discovered that part of a collagen molecule - lamstatin- inhibits growth of lymphatic cells and their communicating networks. Excessive lymphatic growth occurs in lymphangioleiomyomatosis (LAM)- a fatal disease which affects young women- and many cancers. We have shown that lamstatin prevents growth of lymph vessels in a skin tumour in mice and we will investigate if it can prevent spread of tumours to other organs which has exciting implications for the treatment of cancer.
Characterisation Of Conserved Sox18-dependent Genes In Lymphatic Vascular Development
Funder
National Health and Medical Research Council
Funding Amount
$401,355.00
Summary
Lymphatic vessels are important in a number of diseases including lymphoedema and cancer. There is a significant gap in our basic understanding of how lymphatic vessels form. We have identified a series of genes that are regulated downstream of the lymphatic master gene Sox18 in mouse lymphatic vessels. This study aims to characterise these genes using complementary model systems. The genes and pathways identified will represent potential therapeutic targets in a number of disease contexts.
The Importance Of VEGF-D, An Angiogenic Protein, For Lymphangiogenesis, Tumor Growth And Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Tumors attract blood vessels to obtain the nutrients for growth. Furthermore, the presence of blood vessels in a tumor enables tumor cells to enter the bloodstream and spread to distant parts of the body - a process known as metastatis that is the major cause of death in cancer patients. The growth of blood vessels - angiogenesis - is the mechanism by which tumors attract the vasculature. The capacity to block tumor angiogenesis would be of great benefit in the clinic as it would restrict both t ....Tumors attract blood vessels to obtain the nutrients for growth. Furthermore, the presence of blood vessels in a tumor enables tumor cells to enter the bloodstream and spread to distant parts of the body - a process known as metastatis that is the major cause of death in cancer patients. The growth of blood vessels - angiogenesis - is the mechanism by which tumors attract the vasculature. The capacity to block tumor angiogenesis would be of great benefit in the clinic as it would restrict both the growth and spread of tumors. Tumor cells attract blood vessels by secreting angiogenic growth factors that stimulate the proliferation of endothelial cells - the cells that form the inner lining of blood vessels. These Vascular Endothelial Growth Factors (VEGFs) are proteins. One VEGF, namely VEGF-D, was discovered in our laboratory at the Melbourne Branch of the Ludwig Institute for Cancer Research. VEGF-D stimulates the growth of blood vessels and possibly lymphatic vessels and is present in the most common human cancers including malignant melanoma and cancer of the breast and lung. We hypothesize that angiogenesis in some tumors is dependent on VEGF-D. Moreover, VEGF-D secreted by tumor cells may stimulate growth of lymphatic vessels - lymphangiogenesis. As metastatic spread often occurs via the lymphatic vessels, tumor lymphangiogenesis induced by VEGF-D may contribute to metastasis. The purpose of the research project is to determine the role of VEGF-D in tumor angiogenesis and lymphangiogenesis. Firstly we will thoroughly characterize the localization of VEGF-D in human cancer. Secondly, we will test VEGF-D for lymphangiogenic activity. Thirdly, the growth and metastatic spread in mice of tumors overexpressing VEGF-D will be analysed. Finally, aspects of VEGF-D biochemistry and gene regulation will be studied to develop strategies for inhibition of VEGF-D action in cancer.Read moreRead less
Defining The Molecular Events That Initiate The Genesis Of Lymphatic Vessels.
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
Lymphatic vessels are a vital component of the cardiovascular system. Abnormalities in the growth and development of lymphatic vessels are associated with human disorders including lymphoedema, cancer and inflammatory diseases. The focus of this application is to determine the molecular events that initiate the construction of lymphatic vessels, with the aim of identifying targets to which novel therapeutics for the treatment of lymphatic vascular diseases could be generated.
Molecular Mechanisms Of Lymphangiogenesis In Development And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
Lymphatic vessels are a vital component of the cardiovascular system and serve several functions critical to embryonic development and adult health. These include: 1. The uptake, transport and return to the bloodstream of tissue fluid and protein. 2. The uptake and transport of lipids from the digestive tract. 3. The transport of cells of the immune system that fight infection. Abnormalities in the development and function of lymphatic vessels are associated with a large number of human diseases ....Lymphatic vessels are a vital component of the cardiovascular system and serve several functions critical to embryonic development and adult health. These include: 1. The uptake, transport and return to the bloodstream of tissue fluid and protein. 2. The uptake and transport of lipids from the digestive tract. 3. The transport of cells of the immune system that fight infection. Abnormalities in the development and function of lymphatic vessels are associated with a large number of human diseases. These include primary and secondary lymphoedema, inflammatory diseases such as psoriasis, rheumatoid arthritis and and asthma, and malignancies of the lymphatic vessels such as lymphangiosarcoma and Kaposi's sarcoma. Lymphatic vessels are also critical for the progression of many forms of cancer, by virtue of the fact that tumour cells exploit lymphatic vessels as a transport route for metastases. Diseases in which lymphatic vessels are involved therefore impact on a significant proportion of the Australian population. Our current knowledge of the mechanisms by which the lymphatic vascular network is constructed during embryonic development, and deregulated in disease states, is extremely limited. Once the molecular mechanisms of disease origin are established, much needed novel therapeutics to treat patients suffering from lymphatic vascular diseases can be designed. Treatments targeted to prevent the aberrant growth of lymphatic vessels are vital to halt tumour metastasis and the progress of inflammatory diseases, while treatments targeted to stimulate the development of new lymphatic vessels are necessary to treat diseases in which lymphatic vessels are hypoplastic, such as lymphoedema. This project aims to advance our understanding of lymphatic vascular development and function, in order to provide the opportunity to benefit patients suffering from all spectrums of lymphatic vascular disease.Read moreRead less
Rhythmicity, Synchronicity And Spasm In Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$614,520.00
Summary
Many cellular systems undergo rhythmical spontaneous chemical and-or electrical activity . This activity, often referred to as pacemaking, is prevalent in many organs underlying brain waves or causing heart beats or rhythmic contractions of smooth muscle. Our studies on pacemaker rhythmicities in smooth muscle have revealed a novel mechanism, one which is entirely different to that responsible for heart pacemaking, the generally held model for electrical pacemakers. We aim to study the mechanism ....Many cellular systems undergo rhythmical spontaneous chemical and-or electrical activity . This activity, often referred to as pacemaking, is prevalent in many organs underlying brain waves or causing heart beats or rhythmic contractions of smooth muscle. Our studies on pacemaker rhythmicities in smooth muscle have revealed a novel mechanism, one which is entirely different to that responsible for heart pacemaking, the generally held model for electrical pacemakers. We aim to study the mechanism in depth so that we can fully describe its operation. This knowledge will provide insight into phenomena such as spontaneous contractions in blood vessels, lymphatic vessels and in the gastrointestinal tract, activities which are the norm and which are likely to have major influence on blood pressure, the propulsion of lymph and gut peristalsis. The knowledge will in the longer term lead to a better understanding of rhythmicities generally as far ranging as uterine contractions during childbirth to brain waves. An understanding of the pacemaker mechanism may also provide a key to understanding debilitating conditions such as vasospasm which can lead to death or serious disability.Read moreRead less
The Role Of Dysregulated VEGFs In Lymphatic And Non-lymphatic Vascular Malformations
Funder
National Health and Medical Research Council
Funding Amount
$389,486.00
Summary
Vascular malformations are abnormal growths of blood vessels that affect hundreds of children born in Australia every year. They range from small birthmarks to large destructive growths that cause chronic pain, bleeding and major deformity. This is the largest ever study to systematically look for the biological drivers that cause these growths so that drug treatments will ultimately be able to replace surgery as the first line treatment.
The Sentinel Lymph Node Territories Of The Whole Body And Their Clinical Implications: A Human Cadaver Study
Funder
National Health and Medical Research Council
Funding Amount
$602,984.00
Summary
Lymph gland screening with isotopes (Lymphoscintigraphy) has revealed unexpected pathways of cancer spread. This study, using an X-ray injection technique in human cadavers, is re-evaluating the outdated Melways Roadmap of lymph vessel pathways. The aims are to give accurate predictions of cancer spread, explain unusual clinical manifestations and to provide a new method of treating lymphoedema, the incapacitating swelling of limbs that may complicate lymph gland surgery or radiotherapy.