Function And Regulation Of ATM: Mechanistic Studies
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the mole ....The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the molecule will be important in its function in the cell. This project is designed to investigate the importance of other domains in the protein and also what it is that causes ATM to be activated. We have developed a methodology which allows us to introduce changes anywhere in the ATM gene and then test the effects of these changes in a biological read-cut assay. This approach will enable us to ascribe functional significance to any region of ATM. We will focus on regions where we have some preliminary evidence for activity. Finally we will carry out a mechanistic study to see how ATM is activated. These data will be useful in future design of molecules to interfere with the function of ATM in applications designed to make tumours more receptive to radiotherapy.Read moreRead less
Mechanisms Regulating Ribosomal Gene Transcription During Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$436,540.00
Summary
After birth the muscle cells of the human heart stop dividing. Subsequent growth of the heart is achieved by increasing the size of preexisting muscle cells. This process is referred to as hypertrophic growth and accounts for the difference in size between the juvenile and adult human heart. However later on in life, particularly during cardiovascular disease states such as high blood pressure, the adult heart may grow above and beyond that normally expected. This uncontrolled growth, results ev ....After birth the muscle cells of the human heart stop dividing. Subsequent growth of the heart is achieved by increasing the size of preexisting muscle cells. This process is referred to as hypertrophic growth and accounts for the difference in size between the juvenile and adult human heart. However later on in life, particularly during cardiovascular disease states such as high blood pressure, the adult heart may grow above and beyond that normally expected. This uncontrolled growth, results eventually in a sick heart which is no longer able to function properly. Such inappropriate growth of the heart is a component of many human cardiovascular disease states and contributes significantly to human morbidity and mortality. Regardless of the cause, hypertrophic growth of the heart results from increased protein synthesis. This is controlled by increased synthesis of ribosomes, the machinery responsible for making proteins. During the course of our studies investigating the regulation of heart muscle cell hypertrophy we have demonstrated that changes in the activity of a protein termed UBF, which is involved in regulating synthesis of ribosomes, correlates with the rate of hypertrophic growth. We have also demonstrated that if we artificially increase the amount of UBF protein in heart muscle cells we can stimulate hypertrophy. These finding indicate that alterations in the amount or activity of UBF may link hypertrophic stimuli to increased growth of the heart. The work described in this study proposes to investigate the signals and pathways which regulate the amount and activity of the UBF protein during hypertrophic growth of heart muscle cells. We hope by understanding the mechanisms by which the heart grows we will be able to design rational therapeutic regimens to combat the abnormal growth of the heart that often accompanies human cardiovascular disease states such as high blood pressure.Read moreRead less
Weight Loss Programs And Subsequent Fertility Rates In An In Vitro Fertilisation (IVF) Program
Funder
National Health and Medical Research Council
Funding Amount
$28,067.00
Summary
Compared with normal weight women, obese women have lower fertility both in natural and IVF cycles. Obesity is a risk factor for many maternal and fetal morbidities. This study will be the first randomised controlled trial aimed at demonstrating the effect on pregnancy rates of a prior weight loss program for obese women undertaking IVF treatment. A 12 week weight loss program including dietary, exercise, education and psychological factors will be initiated in the treatment arm.
Characterisation Of Cumulus Cell Molecular Mediators Of Oocyte Health
Funder
National Health and Medical Research Council
Funding Amount
$451,896.00
Summary
Many women are poorly fertile because of poor egg quality due to age, disease and lifestyle. IVF can assist, but requires large doses of hormone, which can lead to significant health risks. IVM is an alternative lab technique to IVF, but has very poor success. We discovered that synthetic proteins copied from recently discovered egg proteins can be added to the egg and substantially increase IVM success. Answering why will further will aid treatment for infertile women
Generation Of Human Intestinal Stem Cells By Direct Reprogramming
Funder
National Health and Medical Research Council
Funding Amount
$630,391.00
Summary
Intestinal stem cells (ISCs) can give rise to mini guts in vitro with exciting applications for drug screening and cell based regenerative medicine. However, currently the establishment of mini gut cultures requires an invasive procedure. By taking advantage of a revolutionary new predictive algorithm (Mogrify) we will generate ISC directly from somatic and pluripotent cell sources.
Quantitative In Vitro-in Vivo Extrapolation: Realising The Promise
Funder
National Health and Medical Research Council
Funding Amount
$529,509.00
Summary
Most drugs are 'broken down', or metabolised, in the body by enzymes which are located mainly in liver. Knowing the efficiency of drug metabolism in patients is important for the discovery of new drugs and for the rational use of established drugs. This project will develop in vitro, or test-tube, approaches that predict how well a drug is metabolised in humans and whether it will interact with coadminsitered drugs. In turn, this allows prediction of drug dosage and frequency of administration.