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
Heterogeneity In Processing And Signalling By The Notch Family Of Receptors In Vascular Development And Remodelling.
Funder
National Health and Medical Research Council
Funding Amount
$85,716.00
Summary
Formation and remodelling of the blood vessels is a critical feature of development. In addition, numerous disorders including psoriasis, arthritis, blindness, heart and brain ischemia, neurodegeneration, hypertension, pre-eclampsia, respiratory distress and osteoporosis among others are characterised by defective blood vessel patterning. The significance associated with understanding how Notch genes direct blood vessel formation is paramount, as this knowledge will inform future research.
Transcriptional Control Of Blood Vessel Development By Sox18
Funder
National Health and Medical Research Council
Funding Amount
$468,564.00
Summary
Blood vessels play an essential role in maintaining the supply of nutrients to every organ and tissue in the body. Improper development of blood vessels in the embryo can compromise survival of the embryo, and defects in the ability of blood vessels to grow, regenerate and adapt to change during adult life can be life-threatening. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of ....Blood vessels play an essential role in maintaining the supply of nutrients to every organ and tissue in the body. Improper development of blood vessels in the embryo can compromise survival of the embryo, and defects in the ability of blood vessels to grow, regenerate and adapt to change during adult life can be life-threatening. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fundamental importance in the health sciences to gain an understanding of how blood vessels form and regenerate. As a result of our collaborative research efforts, we have discovered a gene, Sox18, that appears to regulate blood vessel development by controlling the formation and-or behaviour of endothelial cells, which line the blood vessels and make them impermeable. Our research so far indicates that MICE WITH DEFECTS IN SOX18 DIE FROM VASCULAR DEFECTS, underlining the importance of this gene. THIS PROJECT IS CONCERNED WITH FINDING OUT HOW SOX18 WORKS - exactly what goes wrong in mice lacking this gene, whether Sox18 can influence endothelial cell behaviour in cell culture, how Sox18 comes to be active in endothelial cells, what genes are switched on by Sox18, and what genes Sox18 co-operates with in its role in endothelial cells. The answers to these questions will not only provide fundamental basic information about how blood vessels development is controlled, but also sow the seeds for possible future therapies in which blood vessel development could be stimulated (eg in wound healing) or suppressed (eg in tumour progression) through pharmaceutical intervention.Read moreRead less
Impact Of The Extraembryonic Tissues On Early Embryonic Development: Genetic Basis Of Abnormal Body Plan
Funder
National Health and Medical Research Council
Funding Amount
$316,326.00
Summary
An important milestone of early development is the attachment (or implantation) of the embryo to the wall of the womb through the action of a specialized population of cells known as the trophoblasts. The early conceptus comprises not only cells that make up the embryo but also those (called extraembryonic cells) that later forms the placenta, and the membranes that wrap around the developing fetus. The placenta and the membranes are indispensable for the normal fetal growth by providing the eff ....An important milestone of early development is the attachment (or implantation) of the embryo to the wall of the womb through the action of a specialized population of cells known as the trophoblasts. The early conceptus comprises not only cells that make up the embryo but also those (called extraembryonic cells) that later forms the placenta, and the membranes that wrap around the developing fetus. The placenta and the membranes are indispensable for the normal fetal growth by providing the effective nourishment and protection for the developing fetus. Recent studies in the mouse have revealed that normal development of the recently implanted conceptus depends on the reciprocal interaction of the embryonic and extraembryonic cells. Abnormal embryo may form if the non-embryonic cells do not differentiate normally, as seen in the situation when an X-chromosome is lost from the female embryo (as in 45X0 Turner syndrome) and in early conceptus that carries a gene mutation that affects the production of growth factors by the extraembryonic cells. Functional deficiency of the extraembryonic cells might be a cause for early pregnancy loss where the conceptus has successfully implanted but the embryo fails to form. The remarkable conservation of the molecular mechanism that controls mammalian development allows us to use the mouse embryo as a genetic model for human development. The proposed project is designed to examine in a laboratory mouse model the molecular and cellular factors that regulate the activity of the extraembryonic cells. Specifically, we focus on a gene known as Sox17, which may be involved with the differentiation of the extraembryonic cells. We will study the impact of the mutation of this gene on the development of the early embryo to test the hypothesis that the extraembryonic cells may fulfill an important function in ensuring normal embryo formation, in addition to the other roles of nourishment and mechanical protection of the fetus.Read moreRead less
Control Of Blood Vessel Development By SOX Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Cardiovascular disease is Australia s greatest health problem, with an estimated 3 million Australians suffering a spectrum of conditions from hypertension through to heart failure. Improper development of blood vessels in the embryo can compromise survival of the embryo, and predispose patients to vascular disease after birth. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fu ....Cardiovascular disease is Australia s greatest health problem, with an estimated 3 million Australians suffering a spectrum of conditions from hypertension through to heart failure. Improper development of blood vessels in the embryo can compromise survival of the embryo, and predispose patients to vascular disease after birth. The growth of new blood vessels (angiogenesis) is also an important factor in the ability of solid tumours to grow during the progression of cancer. It is therefore of fundamental importance in the health sciences to gain an understanding of how blood vessels form and regenerate. We discovered a gene, Sox18, that appears to regulate blood vessel development by controlling the formation and-or properties of endothelial cells, which line the blood vessels and make them impermeable. Our research so far indicates that MICE WITH DEFECTS IN SOX18 DIE FROM VASCULAR DEFECTS, underlining the importance of this gene. THIS PROJECT IS CONCERNED WITH FINDING OUT HOW SOX18 WORKS - exactly what goes wrong in mice lacking this gene, whether Sox18 can influence endothelial cell behaviour in cell culture, how Sox18 comes to be active in endothelial cells, what genes are switched on by Sox18, and what genes Sox18 co-operates with in its role in endothelial cells. The answers to these questions will not only provide fundamental basic information about how blood vessels development is controlled, but also sow the seeds for possible future therapies in which blood vessel development could be stimulated (eg in wound healing) or suppressed (eg in tumour progression) by drug treatments.Read moreRead less
Head Development: Genetic Determinants And Tissue Potency
Funder
National Health and Medical Research Council
Funding Amount
$947,116.00
Summary
Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formati ....Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formation of the basic components of the embryonic head in the mouse. Knowledge of the formation of the head in the mouse model is therefore relevant to the understanding of related developmental processes in early human development. This project which involves the application of sophisticated embryological and molecular analyses on mouse embryos generated by transgenesis and genetic manipulation provides a detailed studies of craniofacial morphogenesis in a mammalian model for early human development. The micro-manipulation procedures, embryo culture, fluorescence microscopy and the in situ hybridization are routinely performed in our laboratory, and most of the mouse lines are well established in my laboratory. Experiments proposed for this project that focus on the embryological and molecular analysis of normal and mutant embryos should discover new information on the cellular and molecular mechanisms that regulate head development. The knowledge will also offer insight into the pathogenesis of similar craniofacial malformations in other mutant embryos.Read moreRead less
The Role Of The Transcriptional Regulator, Taube Nuss, In Stem Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$267,200.00
Summary
Cells are born, mature, age, are eliminated and replaced by new cells in many organ systems throughout life. Stem cells constitute the reserve of cells set aside for this regeneration process and also for the repair of damaged tissue. During embryonic development transient stem cell populations exist for the generation of tissues. Stem cells are capable of self-renewing proliferation and are able to give rise to mature cell types (differentiation). The regenerative capacity of stem cells could p ....Cells are born, mature, age, are eliminated and replaced by new cells in many organ systems throughout life. Stem cells constitute the reserve of cells set aside for this regeneration process and also for the repair of damaged tissue. During embryonic development transient stem cell populations exist for the generation of tissues. Stem cells are capable of self-renewing proliferation and are able to give rise to mature cell types (differentiation). The regenerative capacity of stem cells could potentially be used in the treatment of degenerative diseases like Parkinson s disease and muscular dystrophy, if we knew enough about their function. If stem cell proliferation and differentiation into mature cell types could be influenced in a clinical setting, stem cells could be encouraged to replace diseased or dead cells more efficiently than they do normally. In sharp contrast to the potential medical benefits that could be derived from stem cells, our understanding of the molecular mechanisms controlling self-renewal and maintenance of a wide differentiation potential are very limited. We have isolated a new gene, Taube nuss (- empty nut), which is essential for the survival of the first transient stem cell population in the early embryo. In mice, lack of Taube nuss protein results in the death of these stem cells, whereas the differentiated cells of the same embryos survive. Taube nuss is a member of a protein complex called transcription initiation complex. We plan to investigate if Taube nuss plays a role in other stem cell populations. If this is the case, we will not only be able to identify Taube nuss as a new regulator of stem cell function. We would also be able to demonstrate a new regulatory mechanism, namely the involvement of specific transcription initiation complexes in the control of stem cell function.Read moreRead less