Estimation Of Transient Increases In Bleeding Risk Associated With Physical Activity In Children With Haemophilia
Funder
National Health and Medical Research Council
Funding Amount
$102,143.00
Summary
Haemophilia A and B are genetic conditions which affect 1 in 7,000 males in Australia. These disorders cause frequent bleeding due to problems with the clotting factor in blood. Over the past decade there has been a move to administer clotting factor to children with haemophilia in order to prevent bleeds and the consequent damage to joints that occurs when bleeds occur in a joint. Participation in vigorous physical activity and sport is thought to increase the risk of bleeding. Because of this, ....Haemophilia A and B are genetic conditions which affect 1 in 7,000 males in Australia. These disorders cause frequent bleeding due to problems with the clotting factor in blood. Over the past decade there has been a move to administer clotting factor to children with haemophilia in order to prevent bleeds and the consequent damage to joints that occurs when bleeds occur in a joint. Participation in vigorous physical activity and sport is thought to increase the risk of bleeding. Because of this, children are often given clotting factor prior to playing sport. However clotting factor is extremely expensive. For example, a boy wanting to play tennis three times a week would require three injections of cIotting factor per week at a cost of approximately $250,000 a year. To date there is no good evidence about which physical activities are likely to increase the risk of bleeding. If this information was available clinicians would be able to optimise timing of administration of clotting factor so that it is administered prior to activities associated with high risk of bleeds. Another reason to quantify risk of bleeds associated with activity is to inform decisions about participation in physical activity. Every boy with haemophilia wants to know if he can play sport or ride a skateboard or jump on a trampoline. Informed decisions about participation require accurate estimates of risk. This study will use an innovative design to provide, for the first time, accurate estimates of the risk of bleeding associated with physical activity. This information will form the basis for clinical practice guidelines regarding participation in physical activity.Read moreRead less
The Role Of Med12, A Subunit Of RNA Polymerase II Mediator, In Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$495,490.00
Summary
In a screen of zebrafish for mutations in blood cell development, we isolated a mutant called syrah. The mutation causing the blood defect was identified in a gene called med12, which encodes a component of the RNA transcription machinery in cells. To understand how this mutation causes a reduction in blood cells, we will identify the proteins that interact with the med12 protein. Understanding the pathway involved may lead to the discovery of new causes of human congenital blood diseases.
Cell Cycle Regulation, Haemopoietic Stem Cells And Myeloproliferation.
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
My research has focused on understanding how the process of cell division can result in different outcomes for adult blood stem cells. I am interested in determining the role of bone and blood vessels in the regulation of blood stem cells and in the development of blood diseases (myeloprolifertive disease). I will also determine the effects of changing the cell cycle with drugs to improve transplantation of blood stem cells.
The Roles Of Retinoids And Their Receptors In Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, s ....Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, such as gene therapy, have been largely unsuccessful, in part due to the lack of success in growing HSCs outside of the body. In such situations, therefore, determining culture conditions that would enable us to grow HSCs outside of the body are highly desirable. This application is based on the studies of CIA, who recently made the novel discoveries that the vitamin A derivative, all-trans retinoic acid (ATRA) has different effects in the regulation of blood cell production. ATRA is currently used in the treatment of acute promyelocytic leukaemia, as it enhances the maturation of the leukaemic cells. CIA has demonstrated that ATRA has the opposite effect on HSCs, with recent data strongly suggesting that ATRA induces the expansion of HSCs outside of the body. The studies outlined in this proposal seek to further define the mechanisms involved in these effects of ATRA and other vitamin A derivatives (collectively termed retinoids) in the regulation of blood cell production. The first specific aim will determine how retinoids expand HSCs. The second specific aim will explore the roles of the different RARs in the regulation of blood cell production. These studies have direct clinical relevance in improving protocols for transplantation and gene therapy of HSCs. Furthermore, insight gained into the roles of retinoids in blood cell production may also lead to the improvement of treatments of various types of blood disorders.Read moreRead less
Mechanisms Underlying The Effects Of TNFalpha In Bone And Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$589,425.00
Summary
Recent studies have identified that bone plays an important role in blood cell production. We have discovered that elevated levels of TNF alpha (which increases with ageing and can negatively impact on health) contributes to a blood cell disorder that can progress to leukaemia. There are also reduced numbers of blood stem cells and bone in this mouse model. In these studies we will determine how TNFalpha contributes to blood and bone defects, which may lead to better treatment of such diseases.
We propose to use a number of genetic approaches to identify key mutations involved in Polycythemia vera. We will analyse patient material, use cell lines and mouse models to investigate any new mutations. We also aim to dissect the role of an important blood cell surface receptor and its cooperation with the mutation in JAK2 recently shown to be important in this disease. These approaches will lead to better understanding of the disease and potential new diagnostic and drug strategies.
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the c ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. The failure to respond well to treatment is assessed by a novel molecular genetic technique developed in our laboratory that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. The major goal of this project is to conduct a clinical trial in which this testing procedure is used at an early stage of treatment, and patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. In addition, the project is also directed towards investigating a range of genes known to have a role in drug detoxification. A number of naturally occurring variations exist for these drug metabolising genes and there is evidence suggesting that specific variations or patterns may influence a cancer's response to treatment. We will therefore examine the genetic patterns present in a large cohort of leukaemias and correlate these patterns with response to treatment. It is anticipated that these studies will help define the most appropriate treatment strategies for children with leukaemia. This project therefore has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less