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.
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.
Role Of The Thymus In T Cell Homeostasis During Foetal And Postnatal Life In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool e ....The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. It follows that a mixing of the pool of older mature T cells with new ones just released from the thymus will introduce more variability, and hence greater adaptability into the immune system. We have developed techniques for labeling the thymus in vivo and the entire blood leukocyte pool in vivo using the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled cells and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and mature cells and their progeny together with their tissue homing properties and surface markers for periods of many months. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
Changes In The Fate Of Thymic Emigrants During Foetal And Postnatal Development In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$62,744.00
Summary
SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a l ....SIGNIFICANCE The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cell, has considerable implications for the development of the T cell repertoire. Recent thymic emigrants represent a wide diversity of positively selected thymocytes but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. A high rate of continuous substitution of mature T cells in the peripheral pool with freshly arriving recent thymic emigrants exhibiting newly arising TCR not previously existing will produce higher adaptive capabilities for the immune system. We have developed techniques for labeling the thymus in vivo by intra-thymic injection with the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled recent thymic emigrants and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and their progeny together with their tissue homing properties and surface markers for periods of many months after they leave the thymus. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
Regulation Of Endometrial Angiogenesis And Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$488,273.00
Summary
Unlike almost all other parts of the adult body, the blood vessels of the endometrium (lining of the uterus) grow and breakdown each month as part of the menstrual cycle. The endometrium also has a very unusual distribution of lymph vessels, which are responsible for removing excess fluid from the tissues and also have an important role in the immune system. The overall aim of this research is to understand how growth and regression of these vascular systems are controlled in the endometrium. Th ....Unlike almost all other parts of the adult body, the blood vessels of the endometrium (lining of the uterus) grow and breakdown each month as part of the menstrual cycle. The endometrium also has a very unusual distribution of lymph vessels, which are responsible for removing excess fluid from the tissues and also have an important role in the immune system. The overall aim of this research is to understand how growth and regression of these vascular systems are controlled in the endometrium. The information will have immediate relevance to a number of clinical problems in which abnormal changes in the blood and lymph vascular systems are observed (e.g. tumour growth, wound healing). This includes a number of significant problems relevant to women's health. Non-menstrual bleeding (often termed breakthrough bleeding) is one of the most common gynaecological problems suffered by women, and can be particularly worrying as it may be a symptom of more serious diseases such as uterine cancer. Breakthrough bleeding can occur under a wide range of hormonal conditions and is thought to be due, at least in part, to faulty uterine blood vessel growth. Endometrial cancer is another serious disease and is the most frequently diagnosed malignancy of the female reproductive system. When diagnosed early, this cancer responds well to therapy. However, treatment of this disease is much more difficult when an increase in blood vessel growth is observed and the tumours interact with the lymphatic vascular system. An aim of this research is to investigate changes in uterine blood and lymph vessel growth associated with breakthrough bleeding and endometrial cancer.Read moreRead less
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
Reevaluation Of The Anatomy Of The Human Lymphatic Vessel Network
Funder
National Health and Medical Research Council
Funding Amount
$539,750.00
Summary
The mode of spread of cancer cells from a primary tumour to other parts of the body is still not completely understood, although the lymphatic system is known to be important in this process. Lymph vessels are tiny transparent channels that form a network over the entire body. They transport tissue fluid to regional lymph glands in the neck, armpits, groin, chest and abdomen where the immune response maybe initiated to combat foreign agents such as bacteria and cancer cells. Current knowledge of ....The mode of spread of cancer cells from a primary tumour to other parts of the body is still not completely understood, although the lymphatic system is known to be important in this process. Lymph vessels are tiny transparent channels that form a network over the entire body. They transport tissue fluid to regional lymph glands in the neck, armpits, groin, chest and abdomen where the immune response maybe initiated to combat foreign agents such as bacteria and cancer cells. Current knowledge of the anatomy of these tiny vessels is based on work done by Sappey more than a century ago. There is an urgent need to update this work as many of his conclusions have been found to be inaccurate. We will use our pioneering methods of microsurgical tissue transfer- now being used worldwide - and our extensive experience in delineating fine channels, to address some of the basic questions about the anatomical pathways of spread of cancer. We hope to discover for example: why cancer on one side of the back can spread to glands in the opposite groin or armpit, thought by Sappey to be impossible; why cancer on one side of the tongue can spread to lymph glands on the opposite side of the neck; and why there is sometimes swelling of the limbs following lymph gland ablation by surgery or radiotherapy of glands in the groin or armpit. Currently it is thought that the only major connections with the venous system are at the base of the neck. Our initial work has shown unexpected connections with blood vessels in the periphery and unreported lymphatic vessel pathways between the skin and deep tissues. The results of this research will give information that will aid in localizing and treating the spread of malignancies and will underlie future treatment of obstructed lymph vessels that are the cause of painful, disabling swelling (lymphoedema) of the limbs.Read moreRead less