Year: 2016

Asthma is a chronic lung disease affecting more than 2.8 million Canadians. It is estimated that numbers may rise to 400 million globally by 2025, substantially increasing both human and financial costs.

One possible explanation is that environmental exposures, including diesel exhaust (DE) air pollution (which usually increases as countries develop), may synergize with inhaled allergens in both the development and worsening of asthma, often leading to “lung attacks.” Exposure to air pollution may affect healthy gene expression in the lungs through “epigenetic modifications,” which change how cells “read” DNA. In preliminary studies, we confirmed that DE exposure caused numerous epigenetic changes, but we still need to understand how this causes the worsening of asthma symptoms. Moreover, we do not understand which components of DE (gases or particles) are driving these changes and which are more harmful. Therefore, I will leverage a state-of-the-art human exposure chamber and an ongoing clinical study to determine whether exposure to DE (with or without particles) and specific allergens affects epigenetics and gene expression.

Healthy and mild asthmatic volunteers will be recruited; over the course of four randomly-ordered visits (each separated by a month), they will be exposed for two hours to filtered air, DE, or particle-depleted DE, followed by inhalation of volunteer specific allergen or salt water. After 48 hours, cells lining the lungs will be collected and genetic material will be analysed.

Parallel to this clinical study, I will perform basic research experiments exposing lung cells to DE, and investigate the mechanisms through which these changes may occur. In addition, these experiments will examine how DE alters responses to asthma therapies and thereby the risk of “lung attacks.”

These studies may contribute biological plausibility and deepen our mechanistic understanding of emerging epidemiology, suggesting a role for air pollution in “lung attacks,” asthma development, and clinical outcomes.

Alzheimer’s disease (AD) is the most common cause of dementia. Unfortunately, there are no effective treatments for this devastating disease. The Alzheimer’s Society estimates that without new treatments, 1.4 million Canadians will be living with dementia by 2031.

Patients with AD often experience disrupted circadian rhythms, manifested as disrupted sleep. Although largely attributed to the underlying disease process, recent findings suggest that sleep directly impacts the pathophysiology of AD. A promising, emerging hypothesis for identifying novel treatments is correcting for changes in the body’s internal time-keeping mechanism, the circadian system.

It is largely assumed that disrupted rhythms are caused by the dampening of central suprachiasmatic nucleus (SCN)-driven rhythms; however, bright light and melatonin treatments, which have putative action on central SCN-driven rhythms, have only had limited success improving cognitive and non-cognitive symptoms. Alternatively, AD pathology may be disrupting synchrony between central and peripheral rhythms, which would cause similar symptoms but require different interventions.

Peripheral rhythms control the timing of cellular and metabolic processes in organs (e.g. liver) and brain regions (e.g. hippocampus). Synchrony ensures that physiological processes throughout the body occur at optimal times. In contrast, desynchrony is extremely detrimental to health and affects the clearance and repair mechanisms necessary to combat the misfolded proteins driving pathogenesis.

The goal of my research is to identify the cause of circadian dysfunction and potential targets for interventions. First, I will characterize the circadian phenotype in a mouse model by measuring behavioural rhythms and sleep. Second, I will measure bioluminescence linked to circadian gene expression, as a real-time reporter of oscillators throughout the body and brain. This has never been done in an AD model and allows us to directly evaluate synchrony between oscillators. Third, I will evaluate whether the “hunger hormone” ghrelin, which directly affects circadian rhythms, neuroplasticity, and memory processes, can improve synchrony between oscillators. Finally, in AD patients I will characterize circadian dysfunction and sleep, and evaluate whether ghrelin can aid in restoring circadian synchrony. My project is the first to explore whether the peripheral circadian system can be modulated as a therapeutic intervention in AD.

Brain swelling is a major cause of death following insults such as stroke and traumatic brain injury. This condition is often caused by an underlying swelling of neurons in the brain, leading to cell death. We currently have limited capacity to replace these neurons, and therefore must find ways to reduce swelling-induced cell death. Recent evidence suggests that an ion channel protein, called Panx1, is involved in this process. Ion channels essentially act as conduits between cells and the external environment. These proteins pass important signaling molecules to co-ordinate cellular responses, such as cell growth, movement, or death.

In this project, I will test whether Panx1 conduits promote cell death following neuronal swelling. I will also examine the mechanisms through which Panx1 channels are activated during neuronal swelling. Early experiments indicate that harmful molecules known as reactive oxygen species, which are created within swollen cells, might play a role in this Panx1 activation and neuron death. Reactive oxygen species cause damage to all cellular components, including proteins. Therefore, I will also examine whether these molecules activate Panx1 conduits by modifying parts of the protein structure.

This work contributes to unraveling the complex and still largely unknown mechanisms underlying neuronal swelling and death, and will guide future studies on therapeutic interventions for neuronal death following brain injury.