Genetic Programs Regulated By The Nuclear Hormone Receptor, LXR, In Muscle: Control Of Cholesterol And Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholester ....The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholesterol levels are characteristic of lipotoxic diseases. HDLs have a defensive role in the prevention of atherogenic dyslipidemia by mediating cholesterol efflux from peripheral tissues through the hormone -dependent ATP-binding cassette (ABC) transporters back to the liver for excretion and elimination. Agents that raise the levels of high density lipoprotein cholesterol (HDLc) through cholesterol efflux provide a pharmaceutical solution for the prevention of hypercholesterolemia, atherogenic and cardiovascular disease. These hormone dependent cholesterol and lipid effluxing proteins are regulated by a protein named LXR. Understanding the functional role of LXR in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body cholesterol homeostasis and lipid metabolism. Furthermore, LXR and LXR target genes that facilitate cholesterol efflux and consequently raise HDLc levels are important pharmaceutical targets. Identification of novel LXR targets in skeletal muscle, which has a significant role in insulin sensitivity and the blood lipid profile provides an additional platform for therapeutic intervention.Read moreRead less
Microarray-targeted Candidate Gene Approach To Finding Ovarian Cancer Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$612,933.00
Summary
We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them t ....We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them to be targeted for screening, and for intervention studies, as well as providing fundamental insight into the etiology of ovarian cancer.Read moreRead less
The Role Of UPF3B And Nonsense Mediated MRNA Decay Surveillance In The Pathology Of Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$789,954.00
Summary
Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundam ....Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundamental importance.Read moreRead less
The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, ....Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, and how this will change the state of the cell. We propose here to use the new technique of gene arrays to uncover the programs, or groups of genes, which GH regulates to change important cellular processes. When used in conjunction with cells expressing GH receptor mutants which are unable to signal to defined pathways, we will be able to know which functional families genes are regulated, and how they are regulated. This information will enable us to know how GH regulates cell growth and metabolism, and therfore to understand what goes wrong when GH or its mediator, IGF-1 , are abnormal. We can also use this information to validate small molecules designed to mimic GH through activating its receptor, to be certain that they are acting in the same way as GH.Read moreRead less
Investigating A Novel Genetic Regulator Of Cardiac Rhythm
Funder
National Health and Medical Research Council
Funding Amount
$557,101.00
Summary
Cardiac arrhythmias affect approximately 5% of the population and have a high association with sudden death. Whilst the cause of cardiac arrhythmia is complex, we know that genetic mutations play a role however we don't know all the genes important for cardiac rhythm. It is imperative that we identify all the genes in this process, so we can determine which mutations cause arrhythmia. We have identified a new gene that causes cardiac arrhythmia and seek to understand how it functions.
Systemic lupus erythematosus (SLE) is a condition which causes inflammation in many different organs and can lead to significant suffering and death. Glucocorticoids (GC) are very good at controlling inflammation, however they have severe side effects such as diabetes and bone thinning, and cannot be used long term. This project aims to investigate a protein “GILZ” in patients with SLE. GILZ may have similar anti-inflammatory effects to GC but may not be associated with the same side effects.
Retinoic Acid Receptor-related Orphan Receptors And The Regulation Of Metabolism:insights Into Diabetes And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$760,799.00
Summary
Nuclear receptors (NRs) function as hormone dependent DNA binding proteins important in sustaining human health, highlighted by the array of medicines that target these proteins for human well being. ROR alpha is one such protein that we have shown regulates fat mass, obesity, and glucose tolerance. Obesity and diabetes are often linked with inflammation. We will examine how ROR controls inflammation during metabolic disease.