Functional Analysis Of The P160 Myb-binding Protein - A Regulator Of Multiple Transcription Factors?
Funder
National Health and Medical Research Council
Funding Amount
$376,697.00
Summary
The c-myb gene is a key molecular regulator of normal blood cell production, but alterations to this gene can also lead to leukaemia. The protein (Myb) encode by the c-myb gene acts as a transcription factor, ie, it controls the activity of other genes. There is good evidence that interactions with other proteins can regulate the activity of Myb. Our laboratory has identified what we believe is one such protein - p160 - that binds to a part of Myb that reduces its activity, and thus that is like ....The c-myb gene is a key molecular regulator of normal blood cell production, but alterations to this gene can also lead to leukaemia. The protein (Myb) encode by the c-myb gene acts as a transcription factor, ie, it controls the activity of other genes. There is good evidence that interactions with other proteins can regulate the activity of Myb. Our laboratory has identified what we believe is one such protein - p160 - that binds to a part of Myb that reduces its activity, and thus that is likely to be responsible for regulating Myb. However, it has recently become apparent that p160 interacts with a number of other transcription factors in addition Myb. The primary aim of this project is to elucidate precisely how p160 interacts with Myb and what the consequences of this interaction are. A range of experimental approaches, which range from in vitro to genetic studies, will be employed to do this. We will test a specific role of p160 suggested by our preliminary studies - that of a transporter of transcription factors between the nucleus and the cytoplasm of the cell. Because of the wide range of transcription factors that p160 interacts with, its effects on the function of the cell are likely to be profound. For this same reason, it is difficult to specifically predict the possible medical-health implications of this work However, what we know to date is consistent with a role for p160 as a tumour suppressor gene. Moreover, parts of this project aim to generate genetic information and tools which will help in determining whether p160 does play such a role and generally, in identifying any other associations of p160 with particular diseases.Read moreRead less
Molecular Regulation Of CRH Gene Expression In The Human Placenta
Funder
National Health and Medical Research Council
Funding Amount
$70,285.00
Summary
Approximately 70% of infant death is a result of premature birth. Preterm delivery occurs in 6-10% of pregnancies, and there has been no reduction in this rate in the last 30 years. This is largely because we remain ignorant of how normal and preterm birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotropin releasing hormon ....Approximately 70% of infant death is a result of premature birth. Preterm delivery occurs in 6-10% of pregnancies, and there has been no reduction in this rate in the last 30 years. This is largely because we remain ignorant of how normal and preterm birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotropin releasing hormone, CRH) in the placenta and the length of time the baby is carried in the mother. In women who will deliver prematurely the rise in CRH production occurs earlier and more rapidly, while in women who deliver late the rise occurs more slowly. This work has led to the concept of a biological clock that determines the length of time the fetus will be carried by the mother before birth, and in which production of CRH in the placenta plays a central role. We have been studying how the CRH gene is controlled in placental cells. We have discovered some regions in the DNA of the CRH gene which have important roles in controlling how much CRH is made by the placenta. The experiments described in this project will determine the molecular mechanisms that control the production of CRH in the human placenta. This will be done by examining the DNA sequences involved in controlling the CRH gene and by identifying the proteins that actually perform the regulating functions that result in either increased or decreased amounts of CRH being produced by the placenta. This important information will help us better understand how normal and preterm birth is controlled, and from that knowledge new ways to detect and prevent premature birth can be developed.Read moreRead less
Enhancing Grain Yield Potential and Quality of Lupin. Sustainability of wheat production in Western Australia depends on the continued use of legumes, specifically lupins, in farming systems. The low returns to growers for lupins has jeopardised these sustainable systems. This project aims to gather new information to develop novel genetic strategies to increase yield potential and modify seed composition in lupins, enhancing their commercial worth.
Plant transformation: exploiting anti-apoptosis genes for very high efficiency transformation. Crop improvement through genetic modification depends on the ability to transform target species. The most desirable method is Agrobacterium mediated transformation. However, plant species and cultivars differ significantly in their ability to be efficiently transformed by Agrobacterium. This is particularly true for the economically important cereals. We have discovered that anti-apoptosis genes, whic ....Plant transformation: exploiting anti-apoptosis genes for very high efficiency transformation. Crop improvement through genetic modification depends on the ability to transform target species. The most desirable method is Agrobacterium mediated transformation. However, plant species and cultivars differ significantly in their ability to be efficiently transformed by Agrobacterium. This is particularly true for the economically important cereals. We have discovered that anti-apoptosis genes, which inhibit programmed cell death, dramatically increase the Agrobacterium transformation efficiency in bananas and sugarcane. We will utilise this information and develop the use of these genes to increase the efficiency of transformation in those crops and cultivars that are difficult to transform using Agrobacterium.Read moreRead less
In Vivo And In Vitro Studies Of The Human -308 TNF Promoter Polymorphism.
Funder
National Health and Medical Research Council
Funding Amount
$232,131.00
Summary
The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarif ....The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarify some of these questions, we will generate genetically modified mice that have either of the two genetic forms of the human TNF promoter. These mice will be compared in two models of associated disease, murine Lupus and cerebral malaria. We will also characterise the interactions of TPF1 with other components of the TNF control region. An understanding of the role of TPF1 in controlling TNF expression and an appreciation of the cell types that are able to express the phenotype, will allow the development of more subtle, cell specific strategies to modulate the activity of TNF without completely abolishing expression and may lead to better preventative and therapeutic strategies.Read moreRead less
Patient Toxicity Prediction: Identification Of Mucosal Injury Mediators Using Microarray Technology
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
There is no effective way to identify all patients that will develop toxic side-effects during the course of their cancer treatment. Current pharmacogenetic testing is too narrow. This project aims to examine whole-genome profiles of patient blood to determine if risk markers of toxicity can be identified prior to beginning treatment. I will do this by comparing oesophageal cancer patients who go on to develop severe toxicity with those who only get mild treatment side-effects.
Retrotransposons As Controlling Elements In Mammals: A Screen For Expression In Somatic Cells And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
Differences between individual mammals are generally thought to be due to differences either between their genes, or between their environments. However, in many cases genetic or environmental factors cannot account for differences between individuals. We have studied mice in which dramatic differences between genetically identical individuals are due solely to the activity of a type of transposable element (transposon). There are tens of thousands of similar elements in the genomes of all mamma ....Differences between individual mammals are generally thought to be due to differences either between their genes, or between their environments. However, in many cases genetic or environmental factors cannot account for differences between individuals. We have studied mice in which dramatic differences between genetically identical individuals are due solely to the activity of a type of transposable element (transposon). There are tens of thousands of similar elements in the genomes of all mammals. A large body of evidence demonstrates that transposons can disrupt gene expression. To prevent this from occurring, most organisms have evolved mechanisms to keep transposons silent. However, fragmentary evidence indicates that transposons are at least sometimes expressed in normal and cancer cells. We hypothesize that activity of transposons in mammals alters gene expression sufficiently to cause variation between individuals, and that altered gene expression can cause disease (particularly cancer) and some manifestations of aging. As a first step toward testing this hypothesis, it is essential to acquire more complete information on the expression of transposons in normal and diseased cells. Furthermore, if transposon expression is closely linked to the development or progression of cancer or aging, then the ability to monitor such expression could have diagnostic utility. DNA array technology is coming into wide use to compare patterns of gene expression in different types of cells. We propose to adapt this method to the study of transposon expression. We will clone examples of all known classes of mouse and human transposon, and study transposon expression in: 1. Normal mice, at intervals from the earliest phase of development to old age, and 2. Human cancers of a variety of types. These studies will provide information of fundamental significance for mammalian biology, and also have the potential to lead to improved diagnosis of disease.Read moreRead less
A new paradigm of gene regulation - implications in embryogenesis and disease. The proposed analysis of a new paradigm of gene regulation will provide a new key to understanding genome function and inform some of the most compelling biological issues of our time such as stem cell biology, tissue and organ regeneration and genetic programming. The insights and technologies developed in this program will be widely applicable in biotechnological and pharmacogenomic research in Australia and worldwi ....A new paradigm of gene regulation - implications in embryogenesis and disease. The proposed analysis of a new paradigm of gene regulation will provide a new key to understanding genome function and inform some of the most compelling biological issues of our time such as stem cell biology, tissue and organ regeneration and genetic programming. The insights and technologies developed in this program will be widely applicable in biotechnological and pharmacogenomic research in Australia and worldwide, and assert Australia's leadership in this area of research.Read moreRead less