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Mechanisms Of Haemopoietic Stem Cell Mobilisation: Role Of The Cross-talk Between Bone Marrow And Bone.
Funder
National Health and Medical Research Council
Funding Amount
$461,196.00
Summary
Blood or Haematopoietic stem cells (HSCs) are found in the bone marrow and make all the blood cells we require life-long. This process must be carefully regulated. The production of too many blood cells leads to leukaemia while too little means anaemia. However we still have much to learn on how this regulation occurs. Scientists have recently found that osteoblasts (the cells that normally form bone) are responsible for some of this regulation. In fact osteoblasts create a type of 'home' for HS ....Blood or Haematopoietic stem cells (HSCs) are found in the bone marrow and make all the blood cells we require life-long. This process must be carefully regulated. The production of too many blood cells leads to leukaemia while too little means anaemia. However we still have much to learn on how this regulation occurs. Scientists have recently found that osteoblasts (the cells that normally form bone) are responsible for some of this regulation. In fact osteoblasts create a type of 'home' for HSCs. Our laboratory has recently found that this relationship also works the other way around. That is bone marrow cells themselves regulate osteoblast numbers and thus bone formation. To show this, we used a therapy that forces haematopoietic stem cells to leave the bone marrow and migrate into the blood (a process called mobilisation). Mobilisation is used clinically to harvest large numbers of HSCs for transplantation into cancer patients to prevent bone marrow failure following chemotherapy. To our surprise, we found that when we mobilise HSCs, the rate of bone formation dropped. As osteoblasts (the bone forming cells) are also involved in creating the HSC 'home', we aim to test whether treatments which increase bone formation boost the number of HSCs that are available to be mobilised and collected for transplantation. Thus, by manipulating bone formation we may ultimately be able to improve the long-term survival rates of cancer patients that require high dose chemotherapy and subsequent transplantation. This proposal also aims to better understand (i) how blood-forming cells control bone formation, and reciprocally (ii) how bone-forming cells regulate haematopoietic stem cells in the bone marrow.Read moreRead less
Role Of Macrophages Residing On The Bone Surface In Bone Renodelling And Repair
Funder
National Health and Medical Research Council
Funding Amount
$54,466.00
Summary
To determine if the F4-80+ macrophages that reside on the bone surface, bone lining macrophages (BLMs) are responsible for the detection of apoptotic osteocyte cells and subsequently initiate bone remodelling in response to bone damage.
I am a biochemical geneticist working on inherited disorders that affect the musculoskeletal system. My major focus is determining the molecular basis of muscular dystrophies and bone and cartilage disorders.
The Role Of Hyaluronic Acid, CD44 And Osteopontin In Haemopoietic Stem Cell Biology
Funder
National Health and Medical Research Council
Funding Amount
$472,062.00
Summary
Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC with ....Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC within the BM following transplantation and in regulating their development into mature blood cells. Encapsulating the concept of highly specific, local interactions regulating blood cells is the 'niche' hypothesis in which MC form a specific 'niche'. The current inability to identify HSC in situ makes it impossible to analyse either their distribution or molecules that regulate this process. Circumstantial evidence suggests the presence of HSC 'niches' in close association with the bone. Using a novel approach based on BM transplantation to track cells lodging in the BM, we were the first to report that the lodgement of a transplanted HSC is not a random process, but results in cells of donor origin migrating to the bone-marrow interface. The presence of HA and CD44 on the HSC and CD44 and ostepontin in the marrow microenvironment are critical for this pattern of lodgement. In addition, we now have evidence that HA and osteopontin are important in the maintenance of HSC in their primitive state. This proposal aims to confirm the critical roles and interactions of these three molecules in HSC biology.Read moreRead less
Increasing Haematopoietic Stem Cell Mobilisation By Targeting A Novel Niche Factor
Funder
National Health and Medical Research Council
Funding Amount
$707,218.00
Summary
Transplantation of patients’ own blood stem cells is used to treat many blood cancers. It increases the chance of cure. However the damage caused by chemotherapies used to combat the cancer can compromise stem cell collection and transplantation. Without transplant, these patients are less likely to be cured. This project is to test new drugs that enhance the harvest of blood stem cells for transplantation. These will increase the success rates of transplants and cure in these cancer patients.
The Unfolded Protein Response In Inherited Musculoskeletal Disease - Mechanisms And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$643,607.00
Summary
In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of debilitating inherited bone and cartilage diseases caused by collagen mutations. Our studies will explore the mechanisms of how this stress causes the disease, but importantly will translate these findings by testing a new therapeutic strategy strengthen bones in brittle bone disea ....In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of debilitating inherited bone and cartilage diseases caused by collagen mutations. Our studies will explore the mechanisms of how this stress causes the disease, but importantly will translate these findings by testing a new therapeutic strategy strengthen bones in brittle bone disease.Read moreRead less
Targeting The Hypoxia Sensing Pathway To Improve Hematopoietic Stem Cell Mobilisation And Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$653,313.00
Summary
Transplantation of patients’ own blood stem cells is used to treat many blood cancers. It increases the chance of cure. However the damage caused by chemotherapies used to combat the cancer can compromise stem cell collection and transplantation. Without transplant, these patients are less likely to survive cancer. This project is to test new drugs that enhance the harvest of blood stem cells for transplantation. These will increase the success rates of transplants and cure in these cancer patie ....Transplantation of patients’ own blood stem cells is used to treat many blood cancers. It increases the chance of cure. However the damage caused by chemotherapies used to combat the cancer can compromise stem cell collection and transplantation. Without transplant, these patients are less likely to survive cancer. This project is to test new drugs that enhance the harvest of blood stem cells for transplantation. These will increase the success rates of transplants and cure in these cancer patients.Read moreRead less
The Unfolded Protein Stress Response In Inherited Skeletal Disease: Mechanism And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of skeletal diseases caused by collagen mutations. We will also test how we can use small chemicals to alleviate the damage done to the cells by the misfolded proteins, in the hope that this approach will provide new therapeutic strategies for these disorders.