Structure-function Analysis Of Nuclear Receptor And Cofactor Action: Evidence For A Role In Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a pr ....Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a previously unknown hormone, and metabolic pathway. We are interested in the orphan hormone receptors, Rev-erbA and RVR, orphan members of the receptor superfamily. Rev-erb alpha expression is regulated by fibrates, widely used hypolipidemic drugs, and the circadian cycle. Rev-erbs mediate the regulation of lipid metabolism and peroxisomal beta oxidation. Furthermore, Rev-erbs are acutely induced during brain seizures, postulated to regulate cerebellar plasticity, and involved in growth control. In view of these critical regulatory roles, and the success of reverse endocrinology to date, we intend to complete the structural analysis of the Rev-erb and RVR as a tool to identify the hormone that binds this receptor. Hormone receptors recruit proteins called nuclear receptor cofactors, that function as regulators of gene expression. The cofactors regulate gene expression and development. Furthermore these cofactors, when misregulated result in the onset of disease and carcinogenesis, which underscores the need for achieving a high resolution view of their function in many tissues. Along these lines, we are interested in exmining the function of these cofactors in muscle. Understanding the molecular role of the NR cofactors during muscle differentiation will be a critical step toward elucidating the dysregulation-function of these proteins in muscle diseases, such as rhabdomyosarcoma and inflammatory myopathy that have cofactor deficiency.Read moreRead less
Mineralocorticoid Receptors - Mechanisms Of Ligand- And Tissue- Specific Activation
Funder
National Health and Medical Research Council
Funding Amount
$126,848.00
Summary
Heart disease is a major cause of death and economic burden in Australia and throughout the world. The steroid hormone aldosterone controls salt and water balance, blood pressure and has a significant role in heart failure. Although drugs that block the aldosterone receptor significantly help patients with heart failure, their use is limited by side effects. This work will identify the profile of proteins that promote aldosterone effects and enable the development of heart-specific blockers.
The Role Of Transcriptional Co-activators And Co-repressors During Embryonic Development
Funder
National Health and Medical Research Council
Funding Amount
$82,421.00
Summary
Every creature starts out as a single fertilized egg. The genome directs the embryonic development of the egg by regulating the expression of genes each of which must be turned on or off at the correct time and place. This essential balance between the activation or repression of genes is controlled by groups of proteins, including ‘transcriptional co-activators’ and ‘repressors’. This project aims to better understand the role of these proteins during embryonic development.
The Hippo pathway is a key regulator of tissue growth. It was first discovered in vinegar flies and plays a similar role in mammals. We aim to define the mechanism by which the different transcription factors in the Hippo pathway operate to control tissue growth. These studies will be performed in flies and mammalian cell culture. Our studies will shed light on how tissue growth is controlled, and have the potential to inform the way that we treat human cancers and tissue growth disorders.
Understanding How GATA2 Controls Lymphatic Vessel Valve Development
Funder
National Health and Medical Research Council
Funding Amount
$697,942.00
Summary
Mutations in the GATA2 gene cause human lymphoedema as a result of the crucial role that GATA2 plays in controlling the expression of genes important for building functional lymphatic vessels. Here we aim to gain a complete picture of the cellular and molecular events that are controlled by GATA2 in lymphatic vessels and in particular, in lymphatic vessel valves.
MicroRNA Pathway Control Of Immune Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$631,370.00
Summary
The immune system is comprised of many different cell types, each with a specialised function. Many are short-lived and must be continually replenished throughout life. Abnormalities in this process underlie many human diseases, including immunodeficiency, autoimmunity and cancer. My laboratory seeks to understand the molecular pathways that control development of immune cells and to identify the defects that lead to disease.
Defining The Role Of GATA2 In Lymphatic Vascular Development As A Means To Understanding How GATA2 Mutations Predispose To Human Lymphedema.
Funder
National Health and Medical Research Council
Funding Amount
$718,890.00
Summary
We have discovered that mutations in the transcription factor GATA2 result in human primary lymphedema, a debilitating disorder resulting from the failure of lymphatic vessels to return tissue fluid to the bloodstream. The goal of this application is to define the role of GATA2 in lymphatic vessels, in order to understand how GATA2 mutations cause lymphedema. Ultimately, we aim to identify targets to which desperately needed therapeutics for the treatment of lymphedema could be generated.
Characterisation Of A Newly Identified, Indispensible, Transcriptional Regulator Of Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$535,224.00
Summary
Lymphatic vessels form via lymphangiogenesis: growth of lymphatics from pre-existing vessels. This process is amenable to therapeutic intervention during metastasis because lymphatics support tumour spread. We discovered a gene that is essential for lymphangiogenesis to occur. We will investigate the control of lymphangiogenesis by this new factor. We aim to understand how it controls lymphatic vessel formation and identify genes within this pathway that have novel therapeutic potential.
Mediator Kinase As A Therapeutic Target For Wnt/β-catenin Dependent Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$949,907.00
Summary
Colorectal cancer is the third leading cause of cancer mortality in Australia and globally. The Wnt/?-catenin signalling pathway is a well established driver of colon cancer growth in >90% of cases. Using sophisticated genetic screens, we identified CDK8/19 as a colon cancer oncogene and critical regulator of Wnt/?-catenin activity. In this proposal, we will use innovative cancer models in mice and human cancer tissues to investigate newly developed CDK8/19 inhibitors for colon cancer therapy ....Colorectal cancer is the third leading cause of cancer mortality in Australia and globally. The Wnt/?-catenin signalling pathway is a well established driver of colon cancer growth in >90% of cases. Using sophisticated genetic screens, we identified CDK8/19 as a colon cancer oncogene and critical regulator of Wnt/?-catenin activity. In this proposal, we will use innovative cancer models in mice and human cancer tissues to investigate newly developed CDK8/19 inhibitors for colon cancer therapy.Read moreRead less
Understanding The Multistep Pathogenesis Of T-cell Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$701,992.00
Summary
Lmo2 is a transcription factor whose overexpression is a common cause of T-cell leukaemia. This project seeks to identify downstream targets of Lmo2 that cause T-cell leukemia. In addition, the origins and effects of secondary mutations that collaborate with Lmo2 in causing T-cell leukaemia will be determined. This will improve our understanding of how T-cell leukaemia develops and provide new molecular targets for therapy.