Understanding The Mechanism Of Action And Pathophysiological Function Of The NOR1 And Nur77 Orphan Nuclear Receptors
Funder
National Health and Medical Research Council
Funding Amount
$269,250.00
Summary
Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the supe ....Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the superfamily on the basis of their sequence identity, however, the endogenous signaling molecules which bind to these proteins are unknown. The orphan NRs Nur77, NURR1, and NOR1, functions as stress response genes which are induced by a wide range of physiological stimuli Furthermore, the NR4A subgroup of receptors has been implicated in carcinogenesis, neurological disorders; inflammation, diabetes and atherogenesis. The objective of this proposal is to examine the molecular mechanisms that control the regulation of gene expression by the orphan nuclear receptors, Nur77 and NOR-1. Furthermore, we will investigate the pathophysiological function of NOR-1 and Nur77 in muscle. Nur77 and NOR-1 are expressed in skeletal muscle. This major mass tissue accounts for ~40% of total body weight and, is a major site of glucose and fat metabolism. Consequently, this peripheral tissue plays a significant role in insulin sensitivity, and the blood lipid profile. Furthermore, a collaboration with industry has identified NOR-1 as an insulin responsive gene in muscle, which becomes hyper-sensitive to insulin induction in diabetic patients. Additionally, we have exciting evidence that the anti-neoplastic purine anti-metabolite, 6-mercaptopurine activates the NR4A subgroup. Nur77 and NOR-1 represent an exciting challenge, and unlocking the molecular mechanisms that NOR-1-dependent transcription provides the opportunity for identifying novel signaling pathways, and therapeutics.Read moreRead less
Plasticity In The Thalamic Reticular Nucleus During Normal And Altered Postnatal Development
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
Thalamic centres concerned with vision send information through the thalamic reticular nucleus to multiple cortical areas in which different aspects of the visual world are analysed. These cortical areas in turn send connections back through the reticular nucleus to the thalamus. Cortical function ultimately depends on the correct connections being established between the sensory receptors and the thalamus and between the thalamus and cortex. Far from being merely a relay station of peripheral s ....Thalamic centres concerned with vision send information through the thalamic reticular nucleus to multiple cortical areas in which different aspects of the visual world are analysed. These cortical areas in turn send connections back through the reticular nucleus to the thalamus. Cortical function ultimately depends on the correct connections being established between the sensory receptors and the thalamus and between the thalamus and cortex. Far from being merely a relay station of peripheral sensory information the dorsal thalamus modifies and interacts with the flow of information around the brain. The reticular nucleus forms an integral part of this information flow. How these connections develop and are modified by disturbance to the visual pathway is crucial to our understanding of brain function. To this end, we will study the connections between three areas of the brain concerned with vision, the thalamic reticular nucleus, the thalamus and the visual cortices. We will focus our study on the development of the reticular nucleus and the importance of a normal visual environment in establishing the proper connections between different brain areas. The importance of studying normal and abnormal development is that it can provide a description of the kinds of experience leading to specific types of neural abnormalites. This information tells us the degree to which connections are malleable and is of potential clinical importance.Read moreRead less
Do Transcription Factor-RNA Interactions Represent A New Mechanism Of Gene Regulation?
Funder
National Health and Medical Research Council
Funding Amount
$704,242.00
Summary
The aim of this proposal is to investigate the mechanisms through which genes are switched on and off. We hypothesise that transcription factors, a set of proteins that contacts DNA to regulate genes, can also interact with a separate class of molecules known as RNA. An understanding of how genes are switched on and off is central to devising strategies for fighting many diseases in a rational way. Our work will have implications for biotechnology and gene therapy.