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
Determining recurrence risk in breast cancer is crucial, as more than half of all recurrences occur after 5 years. However, optimal management of breast cancer is hampered by the challenges in finding rational preventative and predictive targets. Our vision is to find targets responsible for progenitor cell expansion, as candidates for prevention, and to find markers of relapse, to predict early versus late responders to therapy.
Biased Allosteric Modulators Of Metabotropic Glutamate Receptors: Novel Therapeutic Targets For CNS Disorders
Funder
National Health and Medical Research Council
Funding Amount
$611,534.00
Summary
Metabotropic glutamate receptor 5 (mGlu5) is a major therapeutic target for depression and schizophrenia. The proposed studies will improve our understanding of how drug-like chemicals interact with mGlu5 and therefore change the activity of these receptors and in turn the activity of brain cells leading to therapeutic effectiveness. The research undertaken in this program will allow us to be smarter in developing new mGlu5 drugs that are both effective and have minimal side effects.
Understanding Mechanisms Of Allostery And Biased Agonism At The Adenosine A1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$603,033.00
Summary
This project focuses on an important protein found in the heart. Drugs that activate this protein can protect the heart against damage that occurs after a heart attack, but they all have undesirable side effects. We have discovered a new class of molecule that can protect the heart without these side effects. We now seek to understand how these compounds work at the molecular level. This knowledge can facilitate the design of safer medicines for the treatment of cardiovascular disease.
Understanding Allosteric Modulation And Biased Signalling At Family B GPCRs
Funder
National Health and Medical Research Council
Funding Amount
$428,065.00
Summary
Family B GPCRs are therapeutic targets for drugs treating osteoporosis, hypercalcaemia, Paget’s disease, type II diabetes and are being actively pursued for other diseases that represent major global health burdens. Despite huge financial input, there are no orally available drugs that act on these receptors. This speaks to a lack of mechanistic understanding of how they work. My research focuses on addressing this question and how to exploit these receptors to design and identify better drugs.
Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) infect 200 million and 50 million people world-wide, respectively, and there are no preventative vaccines. The work outlined in this fellowship seeks to understand the structure and function of the major surface proteins of these viruses, their ability to be recognised by the immune system and to develop a novel vaccine for the prevention of HCV.
The Structural Basis For Biased Agonism At The Glucagon-like Peptide-1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$872,536.00
Summary
The glucagon-like peptide-1 receptor plays an essential role in nutrient-regulated insulin release, and is a major target for therapeutic treatment of type 2 diabetes. The binding of different drugs to this receptor can promote distinct signalling profiles inside the cell that can lead to different physiological outcomes. Understanding the mechanistic basis for this will provide a framework to enable rational design of novel, better and safer therapeutics for the treatment of diabetes.
Understanding The Structural Basis For Family B G Protein-coupled Receptor Function
Funder
National Health and Medical Research Council
Funding Amount
$745,082.00
Summary
G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that enable communication from external signals to the inside of cells of the body. Family B GPCRs are a therapeutically important subclass of these receptors and they play crucial roles in bone and energy homeostasis, cardiovascular control and immune response. This grant will uncover fundamental knowledge on how these receptors work, and will enhance future development of therapeutics.