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.
The National NH and MRC Baboon colony provides access to large non-human primates to support Australia's research efforts in diverse scientific areas around the country. These include diabetes research (kidney involvement and prevention of kidney damage, nerve damage and eye damage); treatment options inlcuding gene therapy of blood-bone-marrow cancers; understandng pregnancy changes in blood pressure and the causes of hypertension (high blood pressure) in pregnancy; identification of new techni ....The National NH and MRC Baboon colony provides access to large non-human primates to support Australia's research efforts in diverse scientific areas around the country. These include diabetes research (kidney involvement and prevention of kidney damage, nerve damage and eye damage); treatment options inlcuding gene therapy of blood-bone-marrow cancers; understandng pregnancy changes in blood pressure and the causes of hypertension (high blood pressure) in pregnancy; identification of new techniques for analyis of brain function; the effects of aging on liver function especially with regards to drug metabolism; new therapies for transplantation which would allow more rational and lower-safer drug use for transplant patients; breaking down the barriers to animal-to-human transplantation through assessment of safety and development of new techniques; behavioural aspects of fertility management; vaccine development; development of oral vaccination; the nature of wound healing. There is diverse and wide access to the National NHMRC Baboon colony from research interests around Australia. The use of the animals is at all times approved by the Animal welfare Committee governing the colony, as well as that which governs the researchers involved. All approved projects have been given access to the animals required. The need for non-human primate use as opposed to other animals or other techniques not involving animals is justified to the relvant committees before any project proceeds. The use of the animals therefore adds a dimension to Australian research due to animal similarity to humans physiology or size comparisons. Contributions made by the colony in the last 20 years are listed in the attached references, but understanding physiology at a depth not possible with other animals has changed our thinking about the human condition as a result of primate -based research.Read moreRead less