Dietary Protein-induced DNA Damage In Colon And Consequences For Colorectal Oncogenesis
Funder
National Health and Medical Research Council
Funding Amount
$604,797.00
Summary
This research will explore the effects of dietary protein on genetic damage to cells lining the large bowel and risk of developing colorectal cancer. We will determine the degree and type of DNA damage resulting from increased protein, the cellular response to this DNA damage, whether it increases risk for developing bowel cancer and whether it can be minimised by other foods in both an animal model and humans.
Novel Mechanisms Of Genotoxicity: Bioactivation Of Carboxylic Acid Drugs By UDP-glucuronosyltransferases
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
Before any new pharmaceutical products are approved for clinical use, they undergo extensive testing to demonstrate both efficacy and safety. Part of this testing involves ensuring that, within the body, they are not converted to chemically reactive forms able to damage DNA, since DNA damage can lead to cell toxicity or the development of cancer. Our laboratories have recently identified a new mechanism by which the body converts drugs to reactive chemicals called ester glucuronides. We have sho ....Before any new pharmaceutical products are approved for clinical use, they undergo extensive testing to demonstrate both efficacy and safety. Part of this testing involves ensuring that, within the body, they are not converted to chemically reactive forms able to damage DNA, since DNA damage can lead to cell toxicity or the development of cancer. Our laboratories have recently identified a new mechanism by which the body converts drugs to reactive chemicals called ester glucuronides. We have shown that some ester glucuronides can damage DNA. A large number of different drugs have the potential to form ester glucuronides. However, we do not know whether all ester glucuronides cause DNA damage or, if only some do, what properties determine their DNA damaging potential. In addition, most of the current pre-clinical screening of drugs can not detect DNA damage caused by ester glucuronides. We believe this lack of knowledge is of serious concern. Therefore, this project aims to: i) screen a large number of drugs for ester glucuronide-mediated DNA damage; ii) develop some preliminary methods of predicting the DNA damaging potency of these reactive chemicals; and iii) develop a screening test that may be more suitable for detecting DNA damage by ester glucuronides during pre-clinical testing. Such work is essential to ensure the ongoing safety of all pharmaceutical agents.Read moreRead less
Improving Immunoassays For The Diagnosis Of Latent Tuberculosis Infection In Children
Funder
National Health and Medical Research Council
Funding Amount
$489,006.00
Summary
WHO highlights the urgent need for new tests for tuberculosis (TB). Diagnosis of latent TB infection (LTBI) is vital in children to prevent them developing active TB. A tuberculin skin test has long been used but is not always accurate. More accurate blood tests (immunoassays) have recently been developed which improve the diagnosis of LTBI in adults. However, we have shown that these assays do not work well in children. We aim to improve the performance of immunoassays for diagnosing LTBI in ch ....WHO highlights the urgent need for new tests for tuberculosis (TB). Diagnosis of latent TB infection (LTBI) is vital in children to prevent them developing active TB. A tuberculin skin test has long been used but is not always accurate. More accurate blood tests (immunoassays) have recently been developed which improve the diagnosis of LTBI in adults. However, we have shown that these assays do not work well in children. We aim to improve the performance of immunoassays for diagnosing LTBI in children.Read moreRead less
How Do Glycosaminoglycans Promote The Propagation Of Prions?
Funder
National Health and Medical Research Council
Funding Amount
$512,270.00
Summary
The prion diseases are a group of transmissible, neurodegenerative disorders affecting both humans and animals. The most common form in humans is sporadic Creutzfeldt-Jakob disease (CJD), although acquired (variant CJD) and inherited (familial CJD) forms are recognised. Prion diseases are transmissible to the same species by inoculation with, or dietary exposure to, infected tissues. The infectious agent, referred to as a prion , has not been identified at the molecular level. However, a major c ....The prion diseases are a group of transmissible, neurodegenerative disorders affecting both humans and animals. The most common form in humans is sporadic Creutzfeldt-Jakob disease (CJD), although acquired (variant CJD) and inherited (familial CJD) forms are recognised. Prion diseases are transmissible to the same species by inoculation with, or dietary exposure to, infected tissues. The infectious agent, referred to as a prion , has not been identified at the molecular level. However, a major component of purified prions is an abnormal disease associated form of the host encoded prion protein. Understanding how the disease associated form of the prion protein is generated and how host-derived cofactors contribute to its formation will help in our understanding of the infectious nature of these diseases and in the development of effective therapeutic and prophylactic strategies. Glycosaminoglycans are host-derived components of the extracellular matrix that are associated with prion protein plaques found in the brain tissue of patients with prion diseases. Glycosaminoglycans are believed to influence the transmission of prions and the ongoing propagation of infectivity. In this study the importance of glycosaminoglycans in the formation of the disease associated prion protein and the generation of infectivity will be investigated using both cell-free and cell-based models of prion propagation. The understanding gained from this study will be used to develop a high throughput assay that can be used to detect prion infection prior to the development of clinical disease and within a time frame whereby therapeutic intervention may be effective.Read moreRead less
Growth Factors And Regulatory Genes Controlling Male Spermatogonial Proliferation And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$354,536.00
Summary
In newborn and prepubertal boys the testis contains germ cells which are at a premature stage of development and very suseptible to degeneration especially if the testes fail to descend to the scrotum. The molecules which are responsible for the health of these germ cells have been unknown and only recently the way has been opened for direct study of these factors. This has been made possible by a new assay, developed in our labarotory, in which we can grow these germ cells under defined conditi ....In newborn and prepubertal boys the testis contains germ cells which are at a premature stage of development and very suseptible to degeneration especially if the testes fail to descend to the scrotum. The molecules which are responsible for the health of these germ cells have been unknown and only recently the way has been opened for direct study of these factors. This has been made possible by a new assay, developed in our labarotory, in which we can grow these germ cells under defined conditions. This step forward has highlighted some areas of knowledge which need further research such as identification of the processes which stimulate gonocytes to grow and divide. We need to test growth factors, somatic cell factors and also isolate new genes which are associated with germ cells and their growth. This knowledge will have outcomes in two major areas. First, the new findings could be applied to treatment of infertility resulting from undescended testes in which a stimulus could be given to make the germ cells grow again. Second, work in developing longer term culture of germ cells coupled with introduction of mutations will enable us to make mutant mice with a specific gene abnormality, similar to transgenic or gene knockout mice. This technological development would prove less expensive and time consuming with more reproducible and direct outcomes. Mutant mouse technology is a powerful tool to determine the effects of individual genes in the whole animal (mouse).Read moreRead less