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Molecular Basis Of Transgenerational Epigenetic Inheritance In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$477,965.00
Summary
While it has long been recognised that it is not just DNA, but chromosomes, that are passed from the gametes to the embryo, the non-DNA component was thought to carry no information with respect to the offspring's ultimate phenotype. However, there is now evidence that the non-DNA component, the epigenetic component, can play a role in the inheritance of phenotype in mammals. This study will attempt to determine the molecular nature of this phenomenon.
Understanding Human Dysmorphology Through Analysis Of ENU Mutant Mice
Funder
National Health and Medical Research Council
Funding Amount
$602,501.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Rapid Identification And Characterisation Of Genes Involved In Skeletal Development
Funder
National Health and Medical Research Council
Funding Amount
$550,536.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Migratory Behaviour And Cell Cycle Length Of Enteric Neuron Precursors
Funder
National Health and Medical Research Council
Funding Amount
$472,249.00
Summary
The activity of nerves in the intestine is essential for gastrointestinal function. Correct development of intestinal neurons requires migration of precursors to the correct location and control of proliferation to achieve correct neuron number. In this project we will identify the mechanisms regulating migration and proliferation of intestinal neuron precursors during normal development, and in mice with defects in intestinal neurons that are models of human motility disorders.
Role Of MicroRNAs In The Control Of MRNA Translation
Funder
National Health and Medical Research Council
Funding Amount
$360,500.00
Summary
This project studies the function of a recently discovered class of ribonucleic acid (RNA) molecules termed microRNAs (miRNAs). They appear to have very important functions in all multicellular organisms, since many of them have undergone little change over hundreds of millions of years. At present we know that miRNAs probably work by regulating the efficiency with which messenger RNAs (mRNAs) are translated into protein molecules. However we do not know how they accomplish this, or which mRNAs ....This project studies the function of a recently discovered class of ribonucleic acid (RNA) molecules termed microRNAs (miRNAs). They appear to have very important functions in all multicellular organisms, since many of them have undergone little change over hundreds of millions of years. At present we know that miRNAs probably work by regulating the efficiency with which messenger RNAs (mRNAs) are translated into protein molecules. However we do not know how they accomplish this, or which mRNAs are regulated by miRNAs. Our work to date has suggested to us that miRNAs may act in combination with one another on mRNAs, so that the effect on a given mRNA depends on just which miRNAs are present, and how abundant they are. We propose to construct a system in which the function of miRNAs can be studied in vitro, using crude cell extracts that are known to perform mRNA translation and related functions. This will, for the first time, make it possible to test miRNAs in carefully controlled conditions, and ask which steps in translation they affect. We will be able to investigate just how the pairing of miRNA and mRNA sequences determines the ability of a miRNA to act on a specific mRNA, and to confirm that a given miRNA actually does regulate a specific mRNA. To facilitate this goal, we will use three methods to isolate mRNAs that are targets of miRNA regulation. Each of these methods relies on the physical interaction of miRNA and mRNAs in cell extracts. In one method, we will attach a tag to a miRNA, and use the tag to pull out associated mRNAs. In another method, we will use an antibody to a protein that is thought to associate with all miRNAs. The antibody should pull out any mRNAs associated with the miRNA-protein complex. Finally, we will identify mRNAs that have responded to the presence of a miRNA by changing the efficiency with which they are translated. These experiments will provide essential knowledge about an extremely important biological system.Read moreRead less
Gene therapy is a novel form of medical treatment in which healthy genes are used to replace defective genes in cells. It is sobering to realise that in the next few years the whole human DNA sequence will be known. Consequently the already large list of genes which are known to cause disease will be greatly expanded through the application of molecular genetics. Surprisingly, however, treatments based on the correction of disease genes in the cells of a patient are not keeping up with expectati ....Gene therapy is a novel form of medical treatment in which healthy genes are used to replace defective genes in cells. It is sobering to realise that in the next few years the whole human DNA sequence will be known. Consequently the already large list of genes which are known to cause disease will be greatly expanded through the application of molecular genetics. Surprisingly, however, treatments based on the correction of disease genes in the cells of a patient are not keeping up with expectations. In attempting to achieve clinically relevant results, viruses (masters of forcing infected cells to do their bidding) have been harnessed to deliver healthy genes into diseased cells. The problem has been that the modified, safe viruses used clinically have not been efficient at achieving sustained production of healthy genes in sufficient numbers of cells. In the studies described , we will attack this problem using a number of different, but complementary approaches. Our main focus will be to facilitate efficient virus entry of appropriate target cells. We have recently been successful in cloning the receptors for two important viruses which can enter human cells. Identification of these receptors gives us clues to methods of improving virus entry. Now that we know the identity of these receptors, we can create tools to define the type of cells that these viruses can readily target.Read moreRead less
The Primary Cilium In Hedgehog Signalling And Disease
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Every mammalian cell has a single protrusion called the primary cilium. Recent studies in mice and humans have highlighted the importance of the primary cilium in disease states affecting the limb, kidney, skeleton, brain, eyes, ears and lungs, as well as obesity and diabetes. We have isolated a novel mouse with a defect in the machinery required for correct functioning of the primary cilium. This mouse has widespread abnormalities and will be used to elucidate the role of cilia in disease.
Role Of L1CAM In Enteric Nervous System Development
Funder
National Health and Medical Research Council
Funding Amount
$374,759.00
Summary
There are millions of nerve cells in the gut. During development, these nerve cells arise from cells (neural crest) that migrate from the developing brain. Neural crest cells migrate into and along the gut. Some humans have a condition called Hirschsprung's disease in which nerve cells are absent from parts of the gut. Afflicted individuals have severe constipation and require surgery. In this study, we will identify the mechanisms controlling neural crest migration in the developing gut.
Function Of Matrix Proteins Important For Storage And Activation Of TGF And TGF -induced Tissue Remodelling And Repair
Funder
National Health and Medical Research Council
Funding Amount
$690,875.00
Summary
The growth factor TGF is important for tissue development and repair, and in diseases such as pulmonary fibrosis, glomerulonephritis, liver cirrhosis, keloid formation and cancers. This project focuses on 2 important matrix proteins first discovered by Dr Gibson, LTBP-2 and ig-h3, that modulate TGF storage and TGF -induced tissue remodelling . We will use knock out mouse and cell culture models to determine the function of these proteins in tissue development and repair, and in diseases.
Fibroblast Growth Factors In The Development Of Forebrain Commissures
Funder
National Health and Medical Research Council
Funding Amount
$497,796.00
Summary
In order to function correctly the two hemispheres of the brain must communicate information. This communication occurs across large fibre tracts called commissures. There are three commissural projections in the forebrain; the corpus callosum, the hippocampal commissure and the anterior commissure. Here we investigate the development of these commissures and provide a comprehensive analysis of the role of several secreted, fibroblast growth factor proteins, in their development.