Achieving Targeted Delivery Of Drugs To Uterine Muscle In Women For The Prevention Of Preterm Labour
Funder
National Health and Medical Research Council
Funding Amount
$469,008.00
Summary
We have patented liposomes targeted to the uterus, which enable us to deliver drugs specifically to the muscle cells of the uterus, increasing safety. The liposomes can be loaded with drugs that either block or promote contractions, creating a versatile drug delivery system that could treat premature labour or postpartum haemorrhage which are major clinical problems. We seek support to demonstrate their effectiveness in mouse and primate models of preterm labour prior to human studies.
Failure-to-progress In Human Labour Results From A Profound Electrical Negativity Of The Uterine Cells: Targeting The Ion Channels Involved
Funder
National Health and Medical Research Council
Funding Amount
$564,541.00
Summary
The incidence of failure to progress in labour has increased in recent years, being linked to the rise in obesity. The result is a significant escalation in the rate of delivery by Caesarean Section (CS) which increases the risk of serious complications during subsequent pregnancies. We have identified dysfunctional systems associated with poor uterine contraction. We now aim to determine the mechanisms underlying these dysfunctional systems to lay the foundations for better therapeutics.
Rhythmicity And Synchronicity In Uterine Smooth Muscle
Funder
National Health and Medical Research Council
Funding Amount
$291,823.00
Summary
Natural birth occurs through rhythmic contractions of the smooth muscle of the uterus. There is surprisingly little understanding of the mechanism of the pacemaker clock that both initiates and times each contraction in a coordinated manner to expel the fetus. This project is to challenge this knowledge gap using our findings on cellular rhythms that herald Ca2+ stores as a major pacemaker mechanism. First, we will use electrophysiology and calcium imaging techniques to test the hypothesis that ....Natural birth occurs through rhythmic contractions of the smooth muscle of the uterus. There is surprisingly little understanding of the mechanism of the pacemaker clock that both initiates and times each contraction in a coordinated manner to expel the fetus. This project is to challenge this knowledge gap using our findings on cellular rhythms that herald Ca2+ stores as a major pacemaker mechanism. First, we will use electrophysiology and calcium imaging techniques to test the hypothesis that rhythmicity and synchronicity of uterine contractions are underpinned by store pacemaking. Second, we will probe the role of current spread between cells via gap junctions as a mechanism of recruitment and will examine whether accessory cells termed interstitial cells subserve a role in pacemaking. These cells are present within the uterine wall but their function is unknown. We will probe their ion channel properties in relation to pacemaking using patch clamp techniques. Third, we will examine the role of labour hormones, such as oxytocin, in augmenting uterine contractions via interaction with the Ca2+ store mechanism and cell recruitment. These studies will provide new and fundamental insights into uterine pacemaking, an outcome that should be of great significance to understanding and better controlling birth-associated complications such as preterm delivery and failure to progress.Read moreRead less
Control Of Uterine Contraction: Role Of Interstitial Cells
Funder
National Health and Medical Research Council
Funding Amount
$587,206.00
Summary
Being born premature may increase risk of below average IQ, poor performance at school and behavioural difficulties in the child, and increased obesity and blood pressure as an adult, predisposing to life long socio-economic disadvantage. We have come up with a new approach to understanding the control of uterine contraction, namely, that cells other than muscle cells, recently identified in the uterine wall, are essential for inducing forceful and orderly muscle cell contraction during labour.
Characterisation Of Immune Regulators In The Human Myometrium.
Funder
National Health and Medical Research Council
Funding Amount
$85,285.00
Summary
Premature birth is a major cause of perinatal death and morbidity. It further predisposes the individual to increased morbidity throughout life. Although the mechanism of birth has been heavily researched with an objective of preventing preterm babies, it is still not fully understood. A major problem has been the lack of suitable and accessible animal models. A key organ coordinating the birth event is the uterine smooth muscle, myometrium. For effective birth and delivery, the myometrium needs ....Premature birth is a major cause of perinatal death and morbidity. It further predisposes the individual to increased morbidity throughout life. Although the mechanism of birth has been heavily researched with an objective of preventing preterm babies, it is still not fully understood. A major problem has been the lack of suitable and accessible animal models. A key organ coordinating the birth event is the uterine smooth muscle, myometrium. For effective birth and delivery, the myometrium needs to be contracting synchronously in a coordinated manner to dilate the cervix while pushing the fetus into position for eventual delivery through the birth canal. This project aims to characterise the molecular events occurring at the myometrium which precedes and precipitates labour. These local changes will be linked with the systemic hormonal changes in order to approach a model for human parturition.Read moreRead less
Understanding Uterine Contractility: What Can We Learn From Obesity?
Funder
National Health and Medical Research Council
Funding Amount
$600,792.00
Summary
The incidence of failure to progress in labour has increased in recent years, being linked to the rise in obesity. The result is a significant escalation in the rate of delivery by Caesarean Section (CS) which increases the risk of serious complications during subsequent pregnancies. We have identified five dysfunctional systems associated with poor uterine contraction. We now aim to determine the mechanisms underlying these dysfunctional systems, particularly those mechanisms in common.
Is Lactic Acid Concentration In Amniotic Fluid A New Predictor Of Labour Dystocia?
Funder
National Health and Medical Research Council
Funding Amount
$682,538.00
Summary
This study will establish whether higher concentrations of lactate in the amniotic fluid of labouring women can be used as a surrogate marker to improve diagnoses of presence or absence of dystocia. Labour dystocia is a serious problem experienced during childbirth, and is one of the main indications for emergency caesarean section or forceps or vacuum delivery. Although dystocia is a common clinical problem, the current lack of a precise definition leads to considerable variation in practice.
Understanding The Regulation Of HERG Potassium Channel In The Myometrium At The Time Of Labour
Funder
National Health and Medical Research Council
Funding Amount
$597,661.00
Summary
We have shown that a potassium channel known as hERG falls precipitously at the time of term labour and that blocking this channel causes powerful uterine contractions. This grant will determine how the expression of this channel is regulated in the myometrium and whether changes in hERG channels also occur in premature labour.
Understanding The Myometrial Transition At Term And Preterm Labour To Guide Tocolysis
Funder
National Health and Medical Research Council
Funding Amount
$808,447.00
Summary
This grant seeks to understand how the muscle cells of the uterus transform at the time of labour. We propose that this transformation is organised by enzymes that modify the histones around key genes. We will test if a similar pathway operates in cases of preterm labour. The results will guide the development of new ways of treating premature labour that will use targeted nanoparticles to deliver siRNA directly to the muscle cells of the uterus.
Optimising Future Human Health By Optimising Birth Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$876,005.00
Summary
Laureate Professor Smith received an AM for his research on human pregnancy and contributions to Indigenous maternal health. His research has dramatically expanded in the last 5 years to include stillbirth, viral infections during pregnancy, early detection of renal disease, the development of targeted nanoparticles for delivery of therapeutics to the uterus, and data-linkage to test the impact of antenatal care. His research seeks to optimise the health of pregnant women and their children.