Child and Reproductive Health

Professor Mitchell is seeking diagnostics and prognostics for preterm labour and delivery, as well as other diseases of pregnancy such as preeclampsia and intrauterine growth restriction. He focusses on the uses of exosomes and eicosanoids in such tests. In related studies he is evaluating milk as a source of exosomes that can be loaded with drugs or nutritional supplements to treat inflammatory diseases of the gut. He extends these studies to diagnostics for fertility in dairy cows (which supply a major proportion of early life nutrition for babies) and as such help the dairy industry and aid the availability of cheap high quality milk.

Projects include:

Early prevention of inflammation related disease: characterisation and use of milk and infant formula
Our belief in the importance of the “first thousand days”, and the critical part that nutrition plays, has led my group to studies evaluating the composition and molecular actions of milk and infant formula. Our studies of exosomes in biological fluids highlight their important role in milk and thus nutrition. To date, we have mainly determined the proteomic contents (cargo) of exosomes however, we are also beginning to explore the role of exosomal microRNA (miRNA). This project will investigate the exosomal content of infant formula, as well as bovine and human milk, and will evaluate the effects of these on cellular function (e.g., inflammatory mediators).

Uses of exosomes as therapeutic delivery systems.
Exosomes are small (40-120 nm), stable, lipid bilayer nanovesicles identified in biological fluids (e.g., in milk, blood, urine and saliva). They contain a diverse array of signalling molecules, including mRNA, miRNA, proteins, lipids and membrane receptors, and they interact with target cells via multiple pathways. The cargo of circulating exosomes can be indicative of a specific tissue’s health status, granting the capacity for use of exosomes as a tool for disease diagnosis. Moreover, they have many of the features desirable of an ideal drug delivery system (e.g., long circulating half-life, the intrinsic ability to target tissues and cross species compatibility). These factors make exosomes them an ideal candidate to be investigated as a vehicle for delivering therapeutics.

We hypothesise that exosomes can be manipulated to carry specific cargo and upon their delivery will alter the function of target cells.

1. Exosomal loading methods will be tested and isolated exosomes will be loaded with specific cargo (e.g., miRNA).
2. Loaded exosomes will be incubated with target cells and functional changes (e.g., changes in gene or protein expression) evaluated.

Activity and potential of cannabidiol and related compounds for the treatment of neuroinflammation
Epilepsy is neurological disorder estimated to affect over 50 million people worldwide. Only 20–30% of epilepsy cases have a suspected cause. The remaining cases of epilepsies arise in the absence of obvious neurological deficits, intellectual disability, or brain injuries. Neuroinflammation has shown to be linked to neurological diseases such as epilepsy. Neuroinflammation is a normal response that helps to maintain equilibrium. When the inflammation continues for an extended period, or is overactive, it can cause cellular abnormalities seen in acute and chronic neurodegeneration and in epilepsy.
This project will investigate the effects of cannabinoid treatment on neural cells. We hypothesise that cannabinoid treatment will decrease neuroinflammation through alterations to the endocannabinoid-related systems/pathways. Exosomal delivery of cannabinoids has the potential to improve the efficacy of drugs on the cells. In addition, this project will address a major obstacle to the accurate identification of endocannabinoids and eicosanoids, which is the similarity between the molecular structures of these compounds and the lack of specific antibodies in traditional immunoassays. This project will utilise mass spectrometry to differentiate each lipid type (e.g., endocannabinoids, eicosanoids prostaglandins) by monitoring characteristic mass fragment pairs for each molecule at their distinct retention times.

Early diagnosis of pregnancy complications using exosomes
Complications of pregnancy, including preterm birth, represent the major causes of foetal and neonatal morbidity and mortality. These complications go on to potentially affect childhood and adult susceptibility to both cardiac and metabolic diseases. Early detection of these disorders is, therefore, essential to improve health outcomes for mother and baby. We hypothesise that the identification and analysis of exosomal cargo isolated from complicated pregnancies will be indicative of a specific tissue’s health status, granting the capacity for use of exosomes as a tool for disease diagnosis.

1. Employ a discovery approach to evaluate the cargo of exosomes isolated from plasma of women with complicated pregnancies.

Improving cow fertility: targeting exosome-responsive pathways
Until recently, genetic selection in dairy cows has focused primarily on milk production traits, with very few countries including functional traits such as fertility in selection indices. Poor reproductive efficiency in dairy herds results in fewer calves, reduced milk production, high involuntary culling rates, and increased cow maintenance costs. The need for, and utility of markers of early onset of diseases (or vulnerability to diseases) has increased dramatically with development of methodologies around biomarker discovery. These biomarkers would have the potential to lead to early intervention and higher survival rates. This project uses exosomes (described above) from plasma of dairy cows as a source of new biomarkers of fertility status.

1. Evaluate plasma derived exosomal cargo from cows with divergent fertility profiles.
2. Determine the effect of the isolated exosomes incubated with target (e.g changes in gene or protein expression).