Erythroid Molecular Cascades Involving The Tyrosine Kinase Lyn
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Mature red and white cells develope from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (Epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for Epo to stimulate them to become mature functio ....Mature red and white cells develope from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (Epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for Epo to stimulate them to become mature functional cells. Recently, we have demonstrated that mice lacking the Lyn gene develope major problems with their red blood cells. We have identified several molecules which interact with Lyn in red blood cells. We have shown that a molecule called Cbp is important for Epo function in individual red blood cells and now we plan to investigate its function in whole animals. We have shown that a new molecule called Arp is important for red blood cell development. This protein moves in and out of the nucleus (where DNA is stored) and may be important in the regulation of genes needed for red blood cells. The third gene (AFAPbeta) is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Since red blood cells have to shrink considerably during their development, the role of AFAPbeta on red blood cell structure will also be investigated. From these experiments we should develop a much better understanding of how the production of red blood cells is controlled and how diseases of red blood cells (such as anaemia) occur.Read moreRead less
Physical, Lifestyle And Psychosocial Determinants Of Spinal Pain Development In Adolescents
Funder
National Health and Medical Research Council
Funding Amount
$682,800.00
Summary
This project aims to understand the development of back and neck pain in adolescence. By the age of 16 around half of all adolescents have suffered back pain and one third have suffered neck pain. For many adolescents this pain is disabling and over a third of sufferers miss school, miss recreation and seek medical help. The current understanding of back and neck pain in adolescence is quite limited - restricting the effectiveness of initiatives to prevent adolescents having to suffer spinal pai ....This project aims to understand the development of back and neck pain in adolescence. By the age of 16 around half of all adolescents have suffered back pain and one third have suffered neck pain. For many adolescents this pain is disabling and over a third of sufferers miss school, miss recreation and seek medical help. The current understanding of back and neck pain in adolescence is quite limited - restricting the effectiveness of initiatives to prevent adolescents having to suffer spinal pain and of treatment of those adolescents unlucky enough to have an episode. Better understanding and interventions for adolescent spinal pain will also have longer term implications by reducing adult spinal pain. Four out of 5 adults will experience spinal pain. In the USA treating adult back pain is the 4th largest health care cost. Many adults with chronic back pain had their first episode during adolescence. A better understanding of spinal pain in adolescence may help prevent it developing into a lifelong disability. We will collect information from 2,000 adolescents on their experience of back and neck pain and on potential physical, lifestyle and psychosocial risk factors. We believe factors such as their posture, muscle capacity, TV and computer use, mental health and social situation all combine to influence whether a person develops back or neck pain. The project is unique as it will not only collect a broad range of information during adolescence, but will also make use of a large database of health, developmental and psychosocial information already collected from these children since birth. With a better understanding of the development of spinal pain we will be able to develop guidelines to help prevent these problems. We will also be able to develop better treatment plans for sub-groups of adolescents with a particular combination of risk factors. Together these initiatives will assist in understanding and breaking the pathway to chronic spinal pain.Read moreRead less
Leukaemia-cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of these is augmented activity of enzymes called tyrosine kinases including members of the Src family. One called Lyn has been implicated in several leukaemias as well as cancer. We have identified a novel mechanism of down-regulating this family of enzymes mediated by small proteins. These may allow us to develop novel therapeutics for cancer-leukaemia treatment.
Dissecting The Pseudoexfoliation Syndrome With Complementary Genetic, Proteomic And Biophysical Strategies
Funder
National Health and Medical Research Council
Funding Amount
$490,352.00
Summary
Pseudoexfoliation syndrome (PEX) is an eye condition in which flaky material deposits in the eye, greatly increasing the risk of cataract and glaucoma which can lead to blindness. PEX is also associated with heart disease, strokes and aneurysms. Cataract surgery in PEX patients has a higher rate of complications. In this project we will determine the nature of PEX material and why it forms. This knowlege will facilitate better diagnosis and treatment of PEX preventing associated blindness.
The Role Of Melanoma Tumour Antigen P97 (Melanotransferrin) In Melanoma Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$563,242.00
Summary
The Role of Melanoma Tumour Antigen p97 (Melanotransferrin) in Melanoma Tumourigenesis Melanotransferrin (MTf) is a homologue of the iron transport protein, transferrin, and was one of the first well characterised melanoma tumour antigens. Our published studies have shown that MTf plays an important role in melanoma tumourigenesis in vivo. In this proposal, we will assess if it is associated with melanoma progression in patient samples and examine its role in melanoma growth and metastasis.
Effects Of Latrepirdine On Beta Amyloid Clearance, Aggregation And Neurodegeneration In Alzheimer�s Disease
Funder
National Health and Medical Research Council
Funding Amount
$512,647.00
Summary
Alzheimer's disease (AD) is becoming more common with our growing aged population and currently no treatment exists that halts disease progress. The increasing health costs of AD underscore the need for development of any treatment that will slow or halt AD pathogenesis. By understanding the mechanisms of action of a drug [latrepirdine] that has recently shown some promise in phase II clinical trials, related drugs that are more specific and potent will be developed.
Characterization Of Novel Regulators Of Erythropoiesis
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature fu ....Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature functional cells. We have identified six molecules which interact with Lyn in red blood cells. We have shown that amolecule called HS1 is important for epo function in individual red blood cells and now we plan to investigate its functions in whole animals, including mice that lack the HS1 gene. We have also shown that a molecule called Trip1 is important for red blood cell development. Interestingly, this molecule also interacts with the thyroid hormone receptor and can influence the effects of epo and thyroid hormone on red blood cell development. The interplay between these two hormones will be looked at in more detail both at the cell and whole animal levels in normal mice and those lacking the thyroid hormone receptor gene. The third Lyn binding molecule we isolated is a novel gene-we have named it ankyrin repeat protein in line with the molecules it is related to. This gene is expressed in red blood cells and we aim to investigate what role it plays in the development of these cells. The fourth gene is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Its role in red blood cell structure will also be investigated. Finally, the last two molecule we have identified are both novel and are unrelated to any other known proteins. As above, the effects of these two molecules on red blood cell development will be investigated.Read moreRead less
The Effect Of Human ApoE Isoforms And ApoE Receptors On The Clearance Of Oligomeric A 42 By Hepatocytes In Vitro
Funder
National Health and Medical Research Council
Funding Amount
$424,801.00
Summary
Alzheimer's disease (AD) is a progressive memory disorder. Increased production of a short peptide called amyloid- (A ) aggregates to form the sticky masses in the brains of AD patients. The amount of A in the brain is a balance between production and clearance. Surprisingly, we recently demonstrated that the liver clears the majority of A . These results connect AD and cardiovascular disease (CVD), enabling current CVD therapeutics to target A clearance by the liver.
Functional Effects Of Polymorphic Variation Of The Aromatase (CYP19) Gene On Enzyme Activity:relationship To Disease
Funder
National Health and Medical Research Council
Funding Amount
$237,708.00
Summary
After menopause, oestrogen synthesis changes from an ovarian to an adipose source by concersion of androgens to estrogens, a process catalyzed by aromatase, the product of the CYP19 gene. We will generate mutants of the CYP19 gene that we have previously found in humans by site-directed mutagenesis and observe the effects of these mutants on aromatase function. This research will help with diagnosis and treatment of breast and other cancers and osteoporosis in humans .
Pharmacology Of Potential Anti-Tumour Agents: Iron Chelators Of The BpT Class
Funder
National Health and Medical Research Council
Funding Amount
$585,455.00
Summary
Pharmacology of Potential Anti-Tumour Agents: Iron Chelators of the BpT Class Cancer cells have a high iron requirement for DNA synthesis and many clinical trials showed Fe chelators are effective anti-cancer drugs. Their potential to act as anti-tumour agents has been confirmed by the entrance of Triapine into widespread NCI clinical trials. In this NHMRC Renewal, we will perform pharmacological and preclinical studies to promote the development of BpT chelators as novel anti-tumour agents.