A Stable Protein:DNA Complex For Development Of Ultrasensitive Diagnostics In Multiplex Format
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
A new technology platform will be developed to carry out diagnostic tests in a multiplex format with increased sensitivity and precision. We recently discovered a very strong interaction between a protein and a particular fragment of DNA. This interaction can be tuned to enable its use for the simultaneous detection of different disease markers in a single assay. This will improve the time and space needed to perform diagnostic tests in laboratories.
Fine Mapping Of The ADH Region For Alcohol Metabolism, Use And Dependence
Funder
National Health and Medical Research Council
Funding Amount
$215,690.00
Summary
It is widely known that alcohol use and alcohol dependence can cause many social problems and morbidity. We know that social and and cultural factors can affect the possibility of becoming alcohol dependent. We also know that inheritance plays a major role in the risk of becoming dependent upon alcohol. Two inherited causes or genes have already been identified as causing some people to avoid alcohol and so have less chance of becoming dependent upon it. Clues as to why this happens come from wh ....It is widely known that alcohol use and alcohol dependence can cause many social problems and morbidity. We know that social and and cultural factors can affect the possibility of becoming alcohol dependent. We also know that inheritance plays a major role in the risk of becoming dependent upon alcohol. Two inherited causes or genes have already been identified as causing some people to avoid alcohol and so have less chance of becoming dependent upon it. Clues as to why this happens come from what happens to alcohol following a drink. The body detoxifies itself of alcohol in the liver. There it is converted to very highly toxic acetaldehyde and this is normally rapidly removed by a protein called aldehyde dehydrogenase. Some people do not have a normally functioning form of this protein and cannot remove the acetaldehyde from their bodies. They suffer unpleasant side effects such as nausea, facial flushing and sickness. Consequently they learn by experience to avoid alcohol use and are less likely to develop dependence. We now know that even people with a normally inherited form of aldehyde dehydrogenase can have a lowered risk of dependence. The rate at which our livers convert alcohol to actetaldehyde is also a key factor. Those who are inherently quick at this process again learn to avoid alcohol, others are more at risk. The hypothesis will be tested with a unique set of twins who have provided us with detailed information on how quickly they detoxify alcohol and of their drinking habits for over 20 years. Collectively they will enable us to determine if there is a major genetic influence on alcohol use and dependence that is caused by inter-individual differences in a gene for alcohol metabolism. The DNA of these twins will be used to locate mutations that we predict have a common effect upon our measures of alcohol detoxification, drinking habits and risk of alcoholism.Read moreRead less
Mapping Of Genetic Traits In Experimental Models Using Databases
Funder
National Health and Medical Research Council
Funding Amount
$237,750.00
Summary
The project aims to detect genes that influence human traits. These traits could be a disease such as diabetes or they may be much less sinister, representing hearing range as an example. Many of these traits are difficult to detect because they are governed by many genes which may also interact with the environment to influence the trait. In order to detect genes in these traits we would like to simplify the complex interactions by eliminating the environment as a potential cause or concentrati ....The project aims to detect genes that influence human traits. These traits could be a disease such as diabetes or they may be much less sinister, representing hearing range as an example. Many of these traits are difficult to detect because they are governed by many genes which may also interact with the environment to influence the trait. In order to detect genes in these traits we would like to simplify the complex interactions by eliminating the environment as a potential cause or concentrating on a particular population where the incidence appears to be much greater. In human populations we have no control over the environmental exposures and we cannot restrict their movements. For this reason many genetic studies have been conducted in mice. Many strains of mice have been generated. Their environment can be strictly controlled, enabling a much better identification of disease genes. Since mice and humans share much of their genome they also share many of their genes and are often afflicted by the same diseases. Thus if we identify genes in mice we have a very good chance of identifying the equivalent human genes. The completion of sequencing for the human genome is being closely followed by the completion of the mouse genome, precisely because mice have been used for over 100 years for genetic studies. The data generated from these sequencing efforts and prior genetic studies is now accumulating in vast databases. These databases of DNA information can be used to map genes for traits. The idea is to determine the trait measurement for many mice in different strains and compare these trait levels to the DNA state (genotype) of markers in the genome of the strains. If these are associated it indicates that the marker is situated close to a gene influencing the trait. This narrows the search considerably. Without this strategy we would have the daunting task of identifiying trait genes from many thousands of potential candidates.Read moreRead less
Functional Variants Of RUNX2 Related To Bone Density
Funder
National Health and Medical Research Council
Funding Amount
$451,938.00
Summary
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ....Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ancestral form of this gene. We now need to know how this change in this promoter alters bone density and we are following up on observations that other important transcription factors bind to the variable site in the promoter. Furthermore, we have assembled a large collection of samples from people who have had extensive measures of bone density and arthritis in order to accurately measure the impact of this gene on bone density, osteoarthritis and bone fracture. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. Such mutations in a region called the Q-repeat are rather common, 1-200 people are carriers. Our data show that these mutant proteins are not as efficient at their task of regulating other genes. We now want to know how this occurs in a molecular sense, since it is known that the Runx2 protein resides in the nucleus of the cell and interacts with many other regulators. This part of the project is being done with one of the world experts on gene regulation in bone cells. Since RUNX2 is a master regulator of the cells that make bone, this gives hope that it may be possible to alter bone formation through this master regulator.Read moreRead less
High scorers on the personality trait neuroticism are at greatly increased risk of major depression and other neurotic disorders. Neuroticism is a personality trait that shows considerable stability over adulthood. It has a strong genetic basis and it seems that the same genes also determine risk of depression, anxiety and other neuroses. By selecting twins and sibs extremely discordant and concordant (EDAC) for neuroticism we can greatly reduce the cost and increase the power to find genes infl ....High scorers on the personality trait neuroticism are at greatly increased risk of major depression and other neurotic disorders. Neuroticism is a personality trait that shows considerable stability over adulthood. It has a strong genetic basis and it seems that the same genes also determine risk of depression, anxiety and other neuroses. By selecting twins and sibs extremely discordant and concordant (EDAC) for neuroticism we can greatly reduce the cost and increase the power to find genes influencing depression. Questionnaire responses and interviews from 15,027 Australian twins and 11,389 of their family members were reviewed to identify individuals with neuroticism scores in the top and bottom 10%. These individuals were invited to participate in a structured psychiatric interview by telephone, and to give a blood sample. Participation and DNA sampling rates were high and there was minimal evident participation bias. DNA was collected from 2,926 individuals from 884 families including 1,333 EDAC sibling pairs and over 795 parents. A preliminary genome scan on one third of this sample yields several linkage peaks suggesting genes of major effect that appear to replicate findings in similar studies conducted in Holland and England. Given these results it is highly desirable that we obtain a genome scan on the remainder of selected extreme sample. Another one third of this sample is currently being genotyped in America and here we request funds to genotype the remaining third. .If we are successful in identifying genes underlying neuroticism, we will also be able to analyse their contribution to depression and anxiety. This could lead to better drug treatments.Read moreRead less
Goodness-of-fit Testing Of Log-link Models For Categorical Outcome Data
Funder
National Health and Medical Research Council
Funding Amount
$260,863.00
Summary
Information about the health consequences of exposure to causal factors is obtained from mathematical models of observed data. Incorrect inferences are possible if the model does not adequately represent the data. Relative risk models are recommended for observations over time on a cohort of subjects, but it is not known how best to assess the adequacy of such models. This project will assess the performance of summary measures of goodness-of-fit when applied to relative risk models.
Design And Analysis Of Interrupted Time Series Studies In Health Care Research: Resolution Of Methodological Issues
Funder
National Health and Medical Research Council
Funding Amount
$307,125.00
Summary
An interrupted time series (ITS) study involves a population observed on multiple occasions before and after the implementation of an intervention program. However, methods for statistical analysis and designing such studies have not been well developed and many statistical analyses of such studies are flawed. This proposal will investigate appropriate methods for design and analysis, and develop guidelines and software for its implementation by health researchers.
MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONG
Funder
National Health and Medical Research Council
Funding Amount
$432,645.00
Summary
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is i ....Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between 1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented, the substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study of fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history documented by questionnaire. The advantage of this type of data is that information from patients with fracture will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the Australian male population at risk for fracture. The information can be used in decision making for the individual and in policy making for the whole population.Read moreRead less
Australian Genomewide Association Study In Osteoporosis
Funder
National Health and Medical Research Council
Funding Amount
$882,722.00
Summary
Osteoporosis is a common condition in which bone strength is reduced due to reduced amount and quality of bone. Reduced bone strength means an increased risk of fracture. Osteoporotic fractures occur in 1 in 2 women and 1 in 3 men in their lifetime, and the likelihood of suffering osteoporotic fracture increases with age. Most of the risk of developing osteoporosis is genetic, but few of the genes involved have been identified. Our goal is to identify those genes.