Our honours projects are focused upon understanding the pathophysiology of respiratory diseases, and in collaboration with other researchers and clinicians use a variety of in-vitro, in-vivo and human clinical studies. If you are interested in respiratory diseases and can't see your dream project listed here please contact us as the projects listed below are just a selection of our interests.
What is special about viral infections in people with COPD?
When most people have a rhinovirus infection they experience symptoms of the common cold. However, when people with chronic obstructive pulmonary disease (COPD) have a rhinovirus infection they often have a life threatening exacerbation. The reason why this occurs is not known.
The two prevailing hypothesise are: 1) in COPD there is an exaggerated inflammatory response to infection (either due to increased pro-inflammatory cytokine production or defective viral clearance cause by an impaired innate immune system), and 2) when cells are infected with a virus they have impaired responsiveness to corticosteroids – the predominant anti-inflammatory used in COPD.
This project will establish if the innate (anti-viral) immune response to rhinovirus is: 1) intrinsically different in lung cells from people with COPD in comparison to cells from people without COPD, and 2) if rhinovirus infection initiates a state of steroid insensitivity.
TECHNIQUES: Cell culture, virus assays, qPCR, Western blotting, ELISA
Do epigenetic changes occur in COPD?
Chronic obstructive pulmonary disease (COPD) is a major global cause of ill-health and mortality which is increasing in prevalence worldwide and constitutes a huge socioeconomic burden. Whilst the aetiology of COPD is multifactorial, the main risk factor in western societies is cigarette smoking. However, why some smokers develop COPD and others do not is unknown.
In-vitro, we have found that lung cells from people with COPD have a very different response to cigarette smoke in comparison to cells from people without COPD. We hypothesise that this differential response is caused by epigenetic modifications. In this project you will investigate which epigenetic changes occur in COPD, and understand the role of these changes in the response to noxious stimuli.
TECHNIQUES: Cell culture, ELISA, molecular biology
THE ROLE OF INNATE IMMUNE RECEPTORS IN COPD.
Chronic obstructive pulmonary disease (COPD) is a chronic airway condition characterized by chronic airway inflammation, destruction of the lung parenchyma (emphysema) and fibrosis of the small airways (small airways disease). Once it develops, COPD is an irreversible and progressive disease. Inhaled corticosteroids have reduced therapeutic efficacy in COPD patients due to high levels of oxidant stress, and bronchodilators provide symptomatic relief but do not prevent the progression of the disease. There is an urgent need to better understand the cellular and molecular mechanisms underlying the airway inflammatory response in COPD. Similar to asthma, COPD arises due to an abnormal airway immune response to environmental pollutants (namely cigarette smoke) and pathogens. There are many overlaps between asthma and COPD, and the asthma/COPD overlap syndrome is now formally recognised as a distinct disease entity.
We have previously established that innate immune receptors (known as TLR4 and RAGE) play a critical role in the inception and progression of asthma induced by inhaled allergens. Interestingly, these receptors are also implicated in the pathogenesis of COPD. In this project, we will use RAGE/TLR4 gene deficient mice to determine whether these receptors mediate the airway immune response to cigarette smoke, a causative factor in COPD. The project will employ the use of a novel nose only exposure inhalation system to develop a mouse model of COPD. Using this sophisticated technology, puffs of cigarette smoke are delivered to mice connected to an inhalation tower. Once disease is induced, analysis of lung function abnormalities will be measured, and airway tissues will be collected to perform analysis of the airway inflammatory response.
Does rhinovirus reduce the efficacy of asthma medications?
During virus-induced asthma exacerbations bronchodilators such as β2-agonists become ineffective. In our previous studies we have found that the infected bronchial epithelium drives this phenomenon, for example it promotes desensitisation of the β2-adrenoceptor on airway smooth muscle cells.
UNDERSTANDING HOW TRAFFIC BASED POLLUTION DRIVES RESPIRATORY DISEASES.
Epidemiological evidence has provided clear links between traffic pollution and both the severity of respiratory viral infections and exacerbations of respiratory diseases such as asthma and COPD. The cellular mechanisms driving this interaction are not known. Traffic pollution contains many noxious stimuli, but particulate matter (PM) which are small particles containing a mixture of noxious chemicals are a particular concern. This is due to the observation that PM can remain airborne for long periods of time, and are small enough to penetrate deep into the lung and gain access to the blood stream.
As independent stimuli particulate matter (PM) from traffic pollution and viral infections are known to increase inflammation but their combined effect is not known. In this project you will use traffic PM collected from sites around Sydney and explore if pre-treatment of lung cells with PM alters the inflammatory response to rhinovirus infection.
ASK-1 inhibitor as a therapeutic target for preventing airway smooth muscle growth in chronic airway diseases
Increased airway smooth muscle (ASM) mass in airway remodeling is a hallmark feature of asthma and COPD. Clinical studies and animal models have demonstrated increased ASM proliferation and growth with the severity of the disease. Current medications control inflammation and reverse airway obstruction effectively yet have limited effect on remodeling. Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is a member of MAP kinase kinase kinase family. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK-1 has been found to be involved in several chronic diseases. Our proposed studies will use both molecular and pharmacological tools to test whether ASK-1 is a potential target for preventing exaggerated ASM cell growth in asthma and COPD. Collectively, these findings establish the anti-mitogenic effect of ASK-1 antagonists and identify a novel class of drugs and signaling pathways that can be targeted to reduce or prevent airway remodeling in obstructive airway disease.
Autophagy as a potential target in fibrotic airway remodeling in asthma
Airway remodeling is one of the most recalcitrant problems in asthma and has no current therapy. While our preliminary data leads us to examine the causal and novel link between autophagy and fibrosis in asthma, we will pursue these questions with the goal of developing novel targeted therapies. Our work has the potential to lead to the following breakthroughs: 1) Use of autophagy inhibitors as a new class of inhaler treatment in asthma, 2) the development of targeted delivery of autophagy inhibitors to the airway cells of interest, 3) Provide a novel treatment for patients at risk for developing airway remodeling in other airways diseases. This is the necessary work needed for new drug development. If successful, work achieved through this proposal may usher in the next novel treatment and perhaps only targeted therapy for airway remodeling.