The Role Of CXCL12 (SDF-1)/CXCR4 In Pathological Angiogenesis And Osteolytic Bone Disease In Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$665,896.00
Summary
Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine mol ....Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine molecule called CXCL12 which acts as a calling card for plasma cells to leave the lymph node and migrate to the BM. Once within the BM, the cells rapidly grow in response to BM-derived growth factors. This rapid growth causes a depletion in oxygen availability within the tumour and it becomes hypoxic. In response to this hypoxia, the tumour expresses a gene called hypoxia-inducible factor-1 (HIF-1) which regulates the expression of many proteins, including the chemokine CXCL12. Our studies show that the abnormal expression of CXCL12 by the plasma cells acts to promote blood vessel formation within the tumour, which in turn leads to greater tumour growth. In addition, our studies suggest that abnormal CXCL12 expression also promotes the recruitment and activation of large numbers of osteoclast (OC) precursors form the peripheral blood. OC are cells which normally remove unwanted or damaged bone. This proposal will study the interplay between HIF and CXCL12 in the establishment and development of MM and the associated bone destruction.Read moreRead less
Blood Protein Biomarkers For Frontotemporal Lobar Degeneration
Funder
National Health and Medical Research Council
Funding Amount
$184,305.00
Summary
This project will assess blood proteins as biomarkers for different pathogenic forms of frontotemporal dementia (FTD), one of the major neurodegenerative dementias with a very rapid disease progression (mean survival 3 years). At present, it is not possible to predict which pathological variant is present in any given patient. We plan to develop blood protein biomarker assays capable of diagnosing the pathology in vivo.
SNAC2: A Randomised Trial Of Extending Sentinel Node Based Management To Women With Larger Or Multifocal Breast Cancers
Funder
National Health and Medical Research Council
Funding Amount
$1,266,430.00
Summary
SNAC2 extends the work begun in SNAC1, which recruited 1,088 women over 4 years. SNAC1 will determine if sentinel node biopsy causes less arm problems than axillary clearance. The goal of SNAC2 is to establish the risk of local recurrence and long term safety of sentinel node biopsy, especially for women with larger or multiple tumours. SNAC2 is needed to determine whether the smaller operation gives cure rates as good as axillary clearance. If it does, then it will become standard practice.
The Role Of RYK And Eph Receptors In Developmental And Tumour Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
The formation of blood vessels (angiogenesis) is a key process in development of the embryo, wound healing, tumour formation-metastases and in the re-vascularisation of ischeamic limbs. The molecules which control these processess are slowly being characterised. In general belong to a family of molecules called growth factors and theri associated receptor present on the surface of a cell. These molecules can control the number, location and function of specific blood vessels within the body. Rec ....The formation of blood vessels (angiogenesis) is a key process in development of the embryo, wound healing, tumour formation-metastases and in the re-vascularisation of ischeamic limbs. The molecules which control these processess are slowly being characterised. In general belong to a family of molecules called growth factors and theri associated receptor present on the surface of a cell. These molecules can control the number, location and function of specific blood vessels within the body. Recently we have discoverd new members of a family of growth fcators called vascular endothelial growth factors, and demonstrated their ability to promote the growth of blood and lymphatic vessels. In this study we set out to examine the role of another family of growth factor receptors, called RYK (for which we have a granted patent in the USA and Australia) in angiogenesis. functional experiments in mice have demonstrated that RYK can associated with a family of receptors called Eph receptors which play a key role in the remodelling of blood vessels during development and injury. Studying these molecules may tell us why blood vessels know' to be in the correct locations in the body and why in certain disease we see vessels of incorrect structure or location. These studies will form a basis of knowledge to develop rational means to manipulate blood vessel formation in the body, using non-surgical methods. The work will also have application to the areas of cleft palate, craniofacial abnormalities and axon pathfinding.Read moreRead less
Improving Immunotherapy By Vascular Targeting And Barrier Alteration
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Tumors grow in part because they escape destruction by the immune system. New blood vessels grow inside tumors by a process called angiogenesis, which then stops cancer-fighting cells in their tracks. We hypothesise that breaking down the blood-tumor barrier will open tumors for attack by the cancer-fighting immune system. This proposal continues our work on reversal of angiogenesis in the context of immunotherapy. We expect these findings to lead to highly effective anti-tumor therapies.
Differences Between Physiological And Pathological Cardiac Hypertrophy Offer New Strategies For Treating Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$335,473.00
Summary
The heart becomes large both in athletes as well as in patients with heart disease and failure. In the first instance, the large (hypertrophied) heart has normal or even increased pumping ability (function) whereas in the patient with heart disease the function is depressed and the heart may fail. My studies are directed towards finding out what is the difference in these 2 situations and what mechanisms are responsible for making one big heart pump well and the other big heart pump poorly. Spec ....The heart becomes large both in athletes as well as in patients with heart disease and failure. In the first instance, the large (hypertrophied) heart has normal or even increased pumping ability (function) whereas in the patient with heart disease the function is depressed and the heart may fail. My studies are directed towards finding out what is the difference in these 2 situations and what mechanisms are responsible for making one big heart pump well and the other big heart pump poorly. Specifically my project hopes to identify the genes and proteins responsible for the differences. I have already identified one such gene and I now plan to manipulate this gene by overexpressing it in animals (transgenic mice) with heart failure. I predict that overexpression of this gene will improve heart function in models of heart failure. If the hypothesis is correct, activating genes that are activated in the athlete's heart maybe a potential tool for improving heart function, quality of life and life span in patients with heart failure.Read moreRead less
Cellular And Molecular Mechanisms Of Human Choroidal And Retinal Vascularisation
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness h ....The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness has motivated the search for a better understanding of how blood vessel growth in the eye is controlled in healthy tissues and how these controls fail in disease. Our proposal addresses this issue directly. Recent work shows that this neovascularization is not only a response to a rise in the local concentration of molecules that induce such angiogenesis, but also requires a fall in the levels of endogenous molecules that inhibit angiogenesis. Our study will investigate the expression of newly identified angiogenic growth factors (VEGFs) and their receptors as well as angiogenic inhibitors (VEGI and PEDF) in the developing and adult human retina and choroid. We will examine the mechanisms by which the human choroid is formed. Our preliminary results suggests the novel insight that vasculogenesis (the formation of blood vessels via transformation of vascular precursor cells) plays a major role the formation of both the human retina and choroid. Further, these exciting results suggest involvement of novel growth stimulators and inhibitors previously not known to play a role in these processes. Our studies will lead to new insights regarding the vascular growth factors and inhibitors that drive this process, thus leading to a rational basis for new therapeutic targets for the treatment of ARMD. The rapid aging of the Australian population and the consequent predicted doubling of ARMD incidence in the next 20 years demonstrates the urgency of our studies.Read moreRead less