The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disea ....Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disease. H2 relaxin is the principal expression product in vivo and has been shown to exert a wide range of physiological responses beyond those normally associated with pregnancy. We have recently discovered another human - H3 - relaxin that is expressed primarily in the brain which strongly suggests a neuropeptide role. Surprisingly, H2 and 3 relaxins each act via different G-protein coupled receptors. We will perform detailed structure-function studies to determine how these relaxins impart their specific biological actions. Modern chemical synthesis protocols will be used to prepare each of these complex peptides in adequate quantities for detailed secondary and tertiary structural study. Analogues containing modified residues and global domains will be prepared and assayed for characteristic relaxin agonist and antagonist activity. Sophisticated biomolecular interaction analyses will be used to identify differences in receptor binding regions for the two relaxins. The results, together with those obtained by three-dimensional structural analysis using NMR spectroscopy, will allow us to ultimately define the key features of the H2 and 3 hormones that are responsible for selective receptor binding and specific relaxin activity. We will then be able to design smaller, more stable, orally active relaxin mimetics. Such compounds will have great potential for therapeutic application in the treatment of fibrosis or as biological and pharmacological probes of relaxin action.Read moreRead less
The Structural Basis Of The Interaction Of Human Relaxins With Their Receptors.
Funder
National Health and Medical Research Council
Funding Amount
$573,807.00
Summary
Relaxin is a peptide that is involved in the regulation of the birth process. It has considerable promise as an anti-fibrotic agent. Recently, another relaxin-like peptide, relaxin-3, was identified and shown to be brain-specific. It modulates the stress response and appetite. Both relaxins act upon different receptors to elicit their biological effects. To exploit their clinical potential, we will determine how these peptides selectively bind and ativate their individual receptors.
Structure-function And Domain Minimization Of Insulin-like Peptide 3, A Novel Member Of The Insulin Superfamily.
Funder
National Health and Medical Research Council
Funding Amount
$288,000.00
Summary
Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selectio ....Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selection. More recent evidence shows that the peptide has clear roles in modulating male and female germ cell maturation. These effects indicate that agonists and antagonists of INSL3 have potential as specific drugs for novel contraceptive approaches or infertility treatments in both sexes. The actions of INSL3 are mediated by interaction with a G-protein coupled receptor known as LGR8. This receptor is expressed in the testes and ovary as well as several other tissues including the brain. However, very little is known about how INSL3 interacts with LGR8 to produce its physiological responses. Consequently, we will determine the structural features of the peptide that are responsible for receptor binding. This will be achieved by use of chemical peptide synthesis of not only INSL3 but also of analogues of the peptide that contain modified residues or domains. These will be assayed for characteristic INSL3 activity and the results, together with those acquired by modern biomolecular interaction analyses, will be used to identify the receptor binding regions for INSL3. This information, together with a determination of the three-dimensional structure of INSL3 by using NMR spectroscopy, will then be disseminated using computer-assisted molecular modelling to design smaller, more stable, orally active analogues. Such mimetics of reduced size that are correspondingly cheaper and simpler to prepare and handle will have great potential for therapeutic regulators of human fertility.Read moreRead less
Validation Of Non-invasive Finite Element Method Based Localization Of Seizure Onset Zone In Epilepsy Using EEG-MEG
Funder
National Health and Medical Research Council
Funding Amount
$87,191.00
Summary
Epileptic seizures in the brain are often focal. If anti-epileptic drugs are ineffective, a deep brain stimulator may be implanted to abort seizures at their onset or the seizure tissue may be removed. This project aims to locate the seizure tissue from non-invasive EEG-MEG recordings of seizure-like brain activity using a realistic computer model of the electromagnetic fields in the brain. Knowing the location more exactly will improve the outcomes of deep brain stimulation and removal surgery.