Molecular Pathology Research - Institute for Respiratory Health

Molecular Pathology Research

About

Pathology is concerned with determining the causes of disease and may be studied at the cellular, sub-cellular or molecular levels.  

Molecular Pathology Research Group is investigating some of the important molecular and cellular pathways involved causing chronic interstitial lung diseases and cancer, and how they might be manipulated to bring about a cure and/or healing.

Many forms of lung disease can be regarded as the interaction between tissue injury and subsequent attempts to heal the affected tissues.

The Molecular Pathology Research Group are committed to assessing the mechanisms regulating interactions between cells, the matrix surrounding cells and the different molecules released following injury. These interactions stimulate cells to respond in different ways, including by proliferation, migration, invasion, differentiation and collagen production. Diseases arising from abnormal tissue repair include asthma, pulmonary fibrosis, chronic obstructive lung disease (COPD), adhesions and cancer. The focus of their work is in two areas:

Firstly, the Group is examining how lung injury leads to the development of fibrosis (scar tissue in the lung). The cause of Idiopathic Pulmonary Fibrosis (IPF) is unknown but it is widely accepted that repeated injury to the epithelium leads to dysregulated healing, initiating a cascade of processes resulting in fibroblast / myofibroblast accumulation and overproduction and deposition of collagen.

Secondly, they are investigating the mechanisms underlying mesothelial healing, and the role of the mesothelial cell and mesothelial stem cell in normal repair; the formation of post-operative adhesions; and the factors that regulate the development and growth of malignant mesothelioma.

Current research projects

STAT3 regulation of cell responses in IPF

The cause of Idiopathic Pulmonary Fibrosis (IPF) is unknown but it is widely accepted that repeated injury to the epithelium leads to dysregulated healing, initiating a cascade of processes resulting in fibroblast / myofibroblast accumulation and overproduction and deposition of collagen.

The Group have pioneered studies identifying the gp130-induced signal transducer and activator of transcription (STAT)3 signalling pathway as pivotal in the development of lung fibrosis. What regulates STAT3-mediate fibrosis is not clear but their current studies are focussing on understanding the role of mediators known to activate the pathway, cell types that may be regulating the mediator response, as well as a possible breakdown in regulation of the naturally occurring inhibitors that normally control the STAT3 response.

Epithelial-mesenchymal cell communication towards new therapeutic targets for fibrosis

The Group continue to dissect the molecular mechanisms and cell signalling pathways driving fibrosis, and together with collaborations at the University of Newcastle, are investigating mitochondrial dysfunction in IPF.

Fibroblast Scenecence as a driver of pulmonary fibrosis

Through a local, national and international collaboration, the Group continues to investigate cross-talk between epithelial cells and fibroblasts and the role this plays in the progression and development of fibrosis.

The Immune regulation of Idiopathic Pulmonary Fibrosis

The Group are aiming to better understand the role of the immune response, in particular, the ability of white blood cells to communicate with other cells in the lung to regulate lung scarring. This project will characterise the immune cell population in a group of patients previously diagnosed with IPF, with the aim of discovering more targeted and effective treatment options.

Investigating the role of specific B cell subsets in chronic lung disease

The Group have previously reported a potential role for B cells in the development of fibrosis. There has been much interest in the contribution of immune cells to fibrotic disease progression with evidence of increased B cell number, activating factors and B-cell associated chemokines reported for interstitial lung diseases. In fact, a recent Phase I clinical trial in IPF therapy is promising, demonstrating improved lung function in patients with severe disease following B cell depletion therapy. The role of B cells and other immune cells in fibrosis remains unknown. Members of the Group are currently using a combination of preclinical models of fibrosis and patient samples to understand the composition and role of the immune system in fibrosis.

This project is ongoing and also involves collaboration as part of the UWA, Helmholtz Zentrum Munich and University College London Collaborative Research Network. Together collaborators from UCL Prof Robin McAnulty, Mr David Pearce and the Olivia Newton-John Cancer Centre (Melbourne); Prof Matthias Ernst and Dr Robert O’Donoghue, A/Prof Prele and her team are investigating the role of B cells in driving fibrosis. A/Prof has recently developed a collaboration with the Dr Ali Oender Yildrim of the Comprehensive Pneumonology Centre, Helmholtz Zentrum Munich, Germany and will explore the role of B cells in other chronic lung conditions including COPD.

miRNAs in mesothelioma

Limited treatment options in Mesothelioma lead to a short median survival and clinical management is hampered by the lack of molecular biomarkers for diagnosis/ prognosis. There is growing evidence that short noncoding RNAs such as microRNA (miRNA), are useful biomarkers in cancer. Studies performed by the Group are trying to determine the diagnostic and prognostic potential of miRNAs in serum and pleural effusion fluids and cells from patients with mesothelioma compared with other diseases. The Unit also worked a project seeking to determine if differentially expressed serum miRNAs are early disease markers. miRNA also have important biological roles within cells so the Group is also looking at the biological significance of certain miRNAs in mesothelioma.

The hedgehog signalling pathway in mesothelioma

Increasing evidence is pointing to the reactivation and aberrant expression of developmental signalling pathways, such as the hedgehog (Hh) pathway, as critical to the pathogenesis of certain cancers. The Group have undertaken a study which demonstrated that Hh pathway signalling is important in the growth of mesothelioma and are examining different antagonists to identify the best possible therapeutic approach to inhibit mesothelioma growth and to elucidate the mechanisms the Hh pathway uses to promote tumour growth. A/Prof Steve Mutsaers and A/Prof Cecilia Prêle have developed a collaboration with Profs Sam Janes and Robin McAnulty, UCL Respiratory and were recently awarded a British Lung Foundation PhD Scholarship for this project. Ms Samantha Arathimou has been employed to undertake these studies investigating the therapeutic potential of small molecule inhibitors of the Hedghog Signalling pathway as part of her PhD studies. In 2018 Ms Arathimou will visit Perth and over 2018-2019 will spend 12 months with the Group as part of this international collaborative research programme.

Recent highlights

  • PhD Candidate, Tylah Miles awarded the Australian Postgraduate Award Scholarship and the Lung Foundation Australia Bill van Nierop PhD Scholarship, 2018.
  • Awarded NHMRC Project Grant for research into epithelial-mesenchymal cell communication; towards new therapeutic targets for fibrosis.
  • Associate Professor Steve Mutsaers awarded the Alan King Westcare Grant 2017 for the effects of infection on mesothelial gene transcription: a role for immune check point regulation in chronic disease.
  • Awarded the UHU Seed Funding Grant for investigating the role of specific B cell subsets in chronic lung disease.
  • Awarded the UHU Collaborative Grant for Mesothelial cell involvement in serosal repair and adhesion formation.

Publications

Our People
The Molecular Pathology Research Group includes senior scientists, postdoctoral researchers, PhD and Honours students.