DoctorStephen Myers

Project Total: $44,698; This project aims to utilise a new method called messenger RNA (mRNA) technology to study the effects of a protein that may be protective in fatty liver disease. Specifically, we aim to: Source primary human liver cell lines from patients with various degrees of fatty liver disease. Develop tools to be able to harness mRNA Technology in the laboratory. Deliver our mitochondrial protein of interest using mRNA technology to the patient derived liver cells and assess the effects on liver function and metabolism. Funded by: Clifford Craig Foundation - Expression of Interest ($44,698); University of Tasmania.

Project Total: $22,714; The Clifford Craig Foundation has opened their expression of interest process for the 2023 granting round. Successful applicants will then be advised to proceed with a full application. This project follows from previous work investigating the role of the mitochondrial gene Acyl-Co-A dehydrogenase family member 10 (ACAD10) in metabolic action. This study will utilise human liver cells in cell culture to assess whether altering the expression levels of ACAD10 improves the ability of the anti-diabetic drug metformin to perform its signalling actions in liver cells. It will also investigate the effect of lipid oversupply to simulate hepatic steatosis and decipher whether ACAD10 could be used to decrease the pathological effect of a high lipid environment on liver cells. Funded by: Clifford Craig Foundation - Grant ($22,715); University of Tasmania.

Project Total: $80,000; The damaging health effects of active and second-hand cigarette smoking are well documented. Tobacco smoke exposure is the primary cause of COPD and lung cancer. However, the prevalence of tobacco smoking is on the gradual decline. In response to this, the tobacco industry is currently changing strategies, shifting the focus from tobacco cigarettes and promoting the safer? alternative in e-cigarettes. e-cigarettes still deliver nicotine and the number of dual users (traditional cigarettes and e-cigarettes) is alarming. We aim to evaluate the effects of e-cigarettes on: 1. Promoting airway inflammation. 2. Airway remodelling changes. 3. Increasing respiratory infections. Funded by: Clifford Craig Foundation - Grant ($80,000); University of Tasmania.

Project Total: $15,794; The aim of this project is to detect early lung function changes in smokers to change disease trajectory. We will achieve this by measuring the following variables: 1.Spirometry (the current reference measure of lung function based on performance of the large airways); 2. Forced Oscillation Technique(FOT; a measure of small airway function); and, 3. Blood biomarkers of respiratory inflammation and degradation of pulmonaryextracellular matrix, in three groups of individuals: 1. patients with chronic obstructive respiratory disease (COPD), 2. smokers with normallung function; and, 3. healthy individuals who have never smoked in order to find the relationship between the measures of spirometry,FOT and biomarkers across the sample population. Funded by: Clifford Craig Foundation - Grant ($15,794); University of Tasmania.

Project Total: $17,607; Insulin resistance (IR) is a disorder where cells do not respond to insulin and therefore glucose and fat metabolism are compromised. IR is present before, and contributes to, the development of type 2 diabetes (T2D) and several pathological conditions and complications including blindness, neurodegenerative disease, heart disease, kidney failure, amputations and reduced quality of life. Despite extensive research, there is challenging uncertainty of the molecular mechanisms of IR. Recently, we have published a role for zinc and the zinc transporter protein ZIP7 in control of glucose metabolism in IR skeletal muscle. However, a major 'gap' in this work is the lack of understanding of how ZIP7 is regulated in IR. Delineating how ZIP7 is regulated is highly significant to understand how this zinc transporter might be targeted pharmacologically and lead to clinical interventions for the treatment of IR. Accordingly, we hypothesise that ZIP7 modulates cellular pathways that control glucose metabolism in IR skeletal muscle and is therefore amendable to clinical intervention for the treatment of IR. Funded by: Clifford Craig Foundation - Grant ($17,607); University of Tasmania.

Project Total: $21,944; The inability to respond sufficiently to insulin gradually erodes our health. Type 2 diabetes (T2D) results from such insulin resistance in peripheral tissues such as skeletal muscle. In fact, skeletal muscle is the major peripheral tissue that accounts for 70-80% of glucose uptake. While there are several theories on how insulin resistance may manifest, the molecular mechanisms are still largely unclear. Given the major impact this disorder has on the health of our communities, there is an urgent need for continued basic science to understand these mechanisms to appropriately design better therapeutics to treat this disorder. Recently, zinc has been highlighted as a critical metal ion implicated in maintaining glucose homeostasis and therefore is a vital target to study its effects on insulin resistance. We have recently published a role for this metal ion in regulating glucose metabolism in skeletal muscle cells through the concomitant action of several cell signalling molecules. However, it is unclear how this is achieved. Accordingly, this study aims to address the molecular mechanisms whereby zinc can contribute to the regulation of glucose metabolism in insulin resistant skeletal muscle. Funded by: Clifford Craig Foundation - Grant ($21,944); University of Tasmania.

Project Total: $100,000; The M1/M2 phenotype balance has also been especially discussed in the cancer literature as an orchestrator of EMT in driving epithelial malignancies. Such new and translatable insights in COPD are an international priority given the current absence of any significant disease trajectory-modifying drug interventions in clinical practice. Here we continue to focus on EMT in COPD, but especially investigating the role of macrophage-associated cytokines in driving EMT in different patient groups leading to new therapeutic targets. Funded by: Rebecca L Cooper Medical Research Foundation - Grant ($100,000); University of Tasmania.

Project Total: $72,727; IPF is a highly destructive lethal disease of the lungs, but with very little information available on the underlying mechanisms. We are going to explore the process of epithelial cell plasticity (or EMT) and a similar process in blood vessel endothelium (Endo-MT). This work will lead to improved diagnosis and treatment of this nasty lung condition. The project brings together well-characterized patients from the Australian IPF registry, blood samples we have collected from them and innovative techniques to reset thinking about the underlying pathological processes active in this illness. Funded by: Clifford Craig Foundation - Grant ($72,727); University of Tasmania.

Project Total: $48,354; IPF is a highly destructive lethal disease of the lungs, but with very little information available on the underlying mechanisms. We are going to explore the process of epithelial cell plasticity (or EMT) and a similar process in blood vessel endothelium (Endo-MT). This work will lead to improved diagnosis and treatment of this nasty lung condition. The project brings together well-characterized patients from the Australian IPF registry, blood samples we have collected from them and innovative techniques to reset thinking about the underlying pathological processes active in this illness. Funded by: Clifford Craig Foundation - Grant ($48,354); University of Tasmania.

Project Total: $21,460; The inability of the body to respond adequately to insulin following a meal has serious consequences on health. Insulin aids in the uptake of glucose into cells, providing the liver with a store of glucose to maintain blood glucose when needed, and as a vital fuel for energy in skeletal muscle. In an insulin-resistant state, cells cannot utilise glucose, which subsequently causes serious medical conditions including obesity, hypertension, cardiovascular disease and type 2 diabetes. Previously, emerging research has shown that zinc and the proteins that transport zinc in cells play a crucial role in activating molecules involved in glucose uptake in skeletal muscle. Recently we have shown that zinc can promote glucose utilisation in the absence of insulin in skeletal muscle. This presents with an opportunity to manipulate zinc metabolism therapeutically to provide an alternative pathway for providing glucose to cells during an insulin-resistant state. Funded by: Clifford Craig Foundation - Grant ($21,460); University of Tasmania.

Project Total: $72,727; Small airway fibrosis is the main contributor to physiological airway obstruction in COPD. The other main airway pathology in COPD is lung cancer; up to 70% of smoking related lung cancer occurs in mild-moderate COPD. EMT may underlie both pathological features; if true this opens up major new therapeutic possibilities. We aim to investigate the effect of pharmacological agents on the EMT in airways of smokers and COPD. Funded by: Clifford Craig Foundation - Grant ($72,727); University of Tasmania.

Project Total: $7,274; This project tests whether weekly exercise/gym sessions improve the health of carers of children with autism and the motor skills of their child. This project has three objectives: 1) to improve the physical health and mental well-being of caregivers of children with Autism Spectrum Disorder (ASD) through a 12 week exercise program 2) to provide an expedited motor skills assessment process for children (2-5 years) with ASD 3) to identify caregiver friendly strategies that can assist in developing and improving the motor skills of children with ASD Funded by: Tasmanian Community Fund - Grant ($7,274); University of Tasmania.

Project Total: $39,206; Small airway fibrosis is the main contributor to physiological airway obstruction in COPD. The other main airway pathology in COPD is lung cancer; up to 70% of smoking related lung cancer occurs in mild-moderate COPD. EMT may underlie both pathological features; if true this opens up major new therapeutic possibilities. We aim to investigate EMT in airways of smokers and COPD. Funded by: Clifford Craig Foundation - Grant ($39,206); University of Tasmania.

Project Total: $25,959; Describe your project: Insulin resistance (IR) is a disorder that is characterised by the failure of cells in the body to respond to insulin and therefore use glucose efficiently as an energy source. Prolonged IR can lead to Type 2 diabetes (T2D), a devastating disease that is intensifying worldwide. T2D is associated with related diseases including heart disease, obesity, mental illness, and cancer. Although IR is well-researched, its molecular mechanisms are still unclear. Recently, studies involving zinc and the proteins that transport zinc in cells (zinc transporters) have been highlighted for their role in regulating genes and proteins involved in disease. Specifically, one zinc transporter designated as Zip7 is involved in regulating zinc in cells and thus preserving cell function. Accordingly, this project aims to understand the molecular mechanisms of Zip7 and how it can be used to reverse IR and could therefore be amendable to treatment options for T2D. Funded by: Clifford Craig Foundation - Grant ($25,959); University of Tasmania.