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
Understanding The Mechanism And Significance Of CXCL16-mediated Protection Of Tumour Cells From CTL-induced Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$524,520.00
Summary
This research will begin to determine the significance of changes in the amount of a recently-discovered protein on the surface of tumour cells. We have shown that an increase in expression of this protein protects tumour cells from destruction by our immune system's killer T cells. The outcome of this research could lead to a better understanding of how the immune system recognises and kills tumour cells, and ultimately, alternate vaccine strategies for tumours.
Chemokines are small molecules that are released by a number of cell types, particularly monocytes, when inflammation occurs. Chronic inflammatory disease is associated with severe bone erosion and loss of bone quality. Surprisingly, chemokines control osteoclast development as well as macrophage activation; even if the osteoclast has formed, blocking chemokine signalling prevents bone resorption. Chemokines are a new and exciting target to control osteoclast formation.
Monocyte Chemotactic Protein-1 (MCP1) And The PTH Anabolic Effect In Bone.
Funder
National Health and Medical Research Council
Funding Amount
$690,435.00
Summary
Chemokines and their receptors are major regulators of cell-cell interactions in many tissues. This project explores the strong increase of monocyte chemotactic protein-1 (MCP1 or CCL2) in bone, in a treatment where parathyroid hormone (a controller of calcium homeostasis) is used to increase bone mass to prevent osteoporosis. MCP1 was previously thought to be an inflammatory regulator, induced during infection and important in autoimmune conditions, so its role in bone was highly unexpected.
Targeting Neurovascular Communication As A Novel Way Of Reducing Vision Loss In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$986,663.00
Summary
Diabetes is a leading cause of blindness. Here, we evaluate whether diabetes causes changes in the way neurons signal to blood vessels, and whether blocking some of the signals from neurons reduces blood vessel abormalities. Overall, this information is critical to our understanding of the early changes that occur during diabetes and whether novel treatments used early in diabetes can prevent long term changes and vision loss.
Molecular And Cellular Mechanisms Of Skeletal Disease Mediated By Plasma Cell Dyscrasias
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in add ....Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.Read moreRead less
Autoimmune-based thrombocytopenia can be a life-threatening adverse event associated with viral load, surgery, drug therapies or the use of the anticoagulant, heparin. This grant will define mechanisms of anti-platelet antibody-dependent platelet activation and assess shedding of platelet-specific glycoprotein (GP)VI as an immediate consequence of this activation, provide a new strategy for evaluating risk of thrombosis in HIT.
Investigation Of The Proinflammatory Function Of Platelets During Ischaemia-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$552,720.00
Summary
Platelets are important blood cells that stop bleeding. Platelets also regulate inflammation by modulating the function of white blood cells. Excessive stimulation of white cells by platelets may cause tissue damage relevant to a broad of cardiovascular diseases, including heart disease and stroke. This grant application aims to investigate the precise mechanism by which platelets promote inflammation during a heart attack or stroke.
The Role Of P62/A170 In Pathological Bone Destruction
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose ....Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62-A172 may play an important part in the switch off-on signals necessary for bone resorbing cells to resorb bone. To this end, we will study the molecular mechanism of P62 in action, and the interaction with its possible partners for the facilitation of abnormal bone resorption. The clinical significance of this project is to: 1) enhance understanding of abnormal bone resorption in Orthopaedic related diseases and conditions. 2) provide a strategy of drug development for the treatment of these disease and conditions.Read moreRead less
Investigation Of A Novel Mechanism Causing Platelet Hyperactivity In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$583,015.00
Summary
Diabetes represents a serious global health crisis, set to explode over the next few decades. A large proportion of deaths associated with Diabetes can be attributed to a high incidence of cardiovascular disease, with diabetic platelets shown to be ‘hyperactive’. We have defined a novel pathway sensitive to the shear forces of blood flow, which leads to platelet hyperactivity in diabetics. We will investigate potential ways to dampen this pathway, which may offer promise as novel treatments for ....Diabetes represents a serious global health crisis, set to explode over the next few decades. A large proportion of deaths associated with Diabetes can be attributed to a high incidence of cardiovascular disease, with diabetic platelets shown to be ‘hyperactive’. We have defined a novel pathway sensitive to the shear forces of blood flow, which leads to platelet hyperactivity in diabetics. We will investigate potential ways to dampen this pathway, which may offer promise as novel treatments for diabetic patients.Read moreRead less