The Role Of Crim1, A Novel TGFb Superfamily Modulator, In Early Vertebrate Patterning, Vascular And Renal Development.
Funder
National Health and Medical Research Council
Funding Amount
$501,300.00
Summary
The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be dele ....The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be deleterious, with their overexpression leading to conditions such as renal fibrosis and cataract. The activity of these growth factors is regulated by many other proteins, including protein antagonists which bind and inactivate them. It is therefore possible that by understanding these antagonists, we can find new ways of altering TGF beta superfamily activity. We have previously identified a novel protein, Crim1, which we have now shown can bind to TGF superfamily members and can reduce their secretion. We believe that Crim1 plays a role in the patterning of the central nervous system, the development of the blood vessels and the kidneys by regulating the TGFbeta superfamily. In this grant we will be investigating what the effect of disruption to Crim1 is on these organ systems and working out which members of the TGFbeta superfamily it is affecting to cause these effects. To do this, we will knock out the gene in zebrafish and characterise the defects found in a mouse line in which the gene has been disrupted. This may be important in developing new ways of activating or inactiviating these growth factors in a number of clinical conditions.Read moreRead less
Genomic And Proteomic Dissection Of The Molecular Basis Of Kidney Development.
Funder
National Health and Medical Research Council
Funding Amount
$454,582.00
Summary
The number of nephrons present in the human adult kidney can vary by threefold. This is likely to be due to slight variations in the rate of nephron formation during development. Evidence is mounting that a reduced number of nephrons can predispose to renal failure later in life in response to stresses such as hypertension or substance abuse. 80,000 new cases of end stage renal failure occur each year in the US, with 25% of these related to hypertension and therefore possibly linked to a low nep ....The number of nephrons present in the human adult kidney can vary by threefold. This is likely to be due to slight variations in the rate of nephron formation during development. Evidence is mounting that a reduced number of nephrons can predispose to renal failure later in life in response to stresses such as hypertension or substance abuse. 80,000 new cases of end stage renal failure occur each year in the US, with 25% of these related to hypertension and therefore possibly linked to a low nephron number. While it is known that the kidney arises through a series of reciprocal inductive events between the metanephric mesenchyme and the ureteric bud, a better understanding of the molecular basis of these events is needed to understand what dictates nephron endowment. The Wilms tumour suppressor protein WT1 is not only mutated in some cases of the childhood kidney cancer, Wilms tumour, but is also critical for the normal development of the metanephros, as demonstrated by knockout experiments in mice. One of the earliest genes expressed in the metanephric mesenchyme, WT1 is thought to prevent this tissue from dying before differentiation, directing it to form the kidney and, postnatally, regulating normal podocyte function. Although known to be a nuclear regulatory protein, the genes directly regulated by WT1 have not been clearly or convincingly delineated. This study aims to directly screen for changes to gene expression and protein production levels induced by WT1. To do so, an array approach unique in its use of a specific array set derived from developing kidney will be used. In concert, additional specific clone sets derived from mouse kidney prior and post the commencement of nephron formation will be constructed and analysed. As WT1 is a nuclear protein involved in splicing, this study will involve a parallel investigation at a proteomic level of changes in spliceosomal proteins in response to changes in WT1.Read moreRead less
Identification Of Genes Important In Myeloid And Haemopoietic Development By Genetic Screening In Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized ....Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized functions. About 50 mutant zebrafish strains exist in which red blood cell development is perturbed - this was easily recognized because the transparency of embryos enabled lack of blood be easily seen. Our new studies aim primarily to recover mutant zebrafish with disorders of white blood cell formation. We have identified methods to recognize failure of white blood cell formation in zebrafish, and will employ these methods to look for inherited disorders that specifically affect white blood cell development in a process called genetic screening. Fish with different sets of randomly mutated genes will be systematically screened to identify those with abnormal white blood cell development. We have tested our approach and identified several mutants affecting white blood cell development. Once these new strains of fish are identified, we will find the genetic lesion responsible for the abnormality in several of the most interesting strains by gene mapping and positional cloning. Hence, the mutant zebrafish identified in the screen will eventually lead to the discovery of new genes important in white blood cell growth and development. The fish themselves will provide insights into the causes of congenital diseases of white blood cells. Since many genes involved in early development are also important in cancer, we believe that newly identified genes will also help understand the causes of abnormal growth of white blood cells in leukaemia.Read moreRead less
The Role Of Non-coding RNAs In Development And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
We have discovered a new mechanism by which genome activity is regulated. This project will test the hypothesis that this mechanism is critical for cell growth and embryonic development. It has the potential to identify new causes of birth defects and may also be relevant to understanding the etiology of other diseases such as cancer, resulting in improvements in diagnosis and management of disorders that present a major health care burden.
The function of menin in mammalian development. This project aims to determine the role of a ubiquitous transcriptional co-regulator, menin, in mammalian development. Mice that lack menin through targeted deletion of the gene die during embryogenesis, but the cause is unknown, although is likely to be due to the abnormal expression of genes usually regulated by this factor. We will determine which genes are inappropriately expressed and responsible for the accompanying developmental defects. Thi ....The function of menin in mammalian development. This project aims to determine the role of a ubiquitous transcriptional co-regulator, menin, in mammalian development. Mice that lack menin through targeted deletion of the gene die during embryogenesis, but the cause is unknown, although is likely to be due to the abnormal expression of genes usually regulated by this factor. We will determine which genes are inappropriately expressed and responsible for the accompanying developmental defects. This knowledge will help us understand the process of development in mammals, including birth defects in humans.Read moreRead less
Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behav ....Discovering mechanisms of primary embryonic tissue migration through live cell imaging and novel genetic approaches. The studies proposed here will provide concepts and knowledge about the molecular basis of cell migration that will impact on diverse aspects of human health, such as the causes and nature of tumour metastasis and our understanding of the developmental basis of birth defects. In addition, understanding cell migration mechanisms will allow us to better predict or control the behaviour of therapeutic stem cells introduced into the body.Read moreRead less
Identification and characterisation of caspase inhibitors. Organisms use a tightly controlled process of cell death (termed apoptosis) to remove dangerous and unwanted cells. Dysregulation of this process can contribute to diseases such as cancer and autoimmune disease. Caspases are protease effectors of apoptosis. Regulation of their activity is vital for effective control of cell survival and death. Using a functional screening system invented by the 1st CI, we aim to isolate and characterise ....Identification and characterisation of caspase inhibitors. Organisms use a tightly controlled process of cell death (termed apoptosis) to remove dangerous and unwanted cells. Dysregulation of this process can contribute to diseases such as cancer and autoimmune disease. Caspases are protease effectors of apoptosis. Regulation of their activity is vital for effective control of cell survival and death. Using a functional screening system invented by the 1st CI, we aim to isolate and characterise novel inhibitors of caspases. Such inhibitors may in time be used as targets for development of therapeutic or diagnostic reagents aimed at manipulating the apoptotic process to diagnose, prevent or treat disease.Read moreRead less
Using integrated frontier and smart technologies to identify new drug targets for parasites causing major diseases in humans and animals. The national/community benefits are (1) enhanced focus on animal and human health biotechnology through the development of anti-parasite compounds and/or vaccines; (2) improved and sustainable control of important parasites with decreased risk of induction of drug resistance; (3) increased profitability of agricultural animal production; (4) consolidation of a ....Using integrated frontier and smart technologies to identify new drug targets for parasites causing major diseases in humans and animals. The national/community benefits are (1) enhanced focus on animal and human health biotechnology through the development of anti-parasite compounds and/or vaccines; (2) improved and sustainable control of important parasites with decreased risk of induction of drug resistance; (3) increased profitability of agricultural animal production; (4) consolidation of a technology platform for further applications in genomics and post-genomics of pathogens of global significance and construction of a pipeline for the validation of drug targets; (5) capturing the benefits from fundamental research and strengthening links between fundamental and applied research; (6) increasing the quality and quantity of scientifically skilled people in biotechnology.Read moreRead less