Defining novel roles for granzyme K in allergic airway inflammation

Asthma is a global health problem that affects over 300,000 British Columbians. It is a group of diseases that is caused by
inflammation of the lung airways, which leads to airway narrowing and breathing difficulties. Inflammation is the body’s normal
response to perceived threats, such as bacteria and viruses. In asthma, the inflammatory response in the lungs is over-sensitized,
disrupting normal lung function. Thus, there is an urgent clinical need to find effective therapies for asthma.
Granzyme K belongs to the Granzyme protein family that plays key roles in many inflammation-associated diseases. Although
granzyme K has been found at elevated levels in the lungs of asthma patients, its role in allergic asthma is widely unexplored.
We propose to examine the role that Granzyme K plays in asthma in established experimental models. Specifically, we will examine
localization of Granzyme K in the lungs and the cells responsible for its production. We will also evaluate how Granzyme K
contributes to the onset and progression of allergic asthma. Our findings will improve our understanding of Granzyme K and the
role it plays in asthmatic lungs. Importantly, this study will evaluate Granzyme K as a candidate drug target for asthma.

Paediatric spinal cord injury in Canada: Using administrative claims data to examine long-term health outcomes and healthcare utilization

A spinal cord injury (SCI) is defined as damage to the spinal cord that results from traumatic (e.g. motor vehicle accidents or falls) or non-traumatic (e.g. spina bifida or tumour diagnosis) causes. Children with SCI often require extensive medical follow-up and rehabilitation, and are at increased risk of adverse health effects (such as bladder issues, respiratory and cardiovascular disorders, and death) compared to children without SCI. Despite presumed increases in the number of Canadian children living with SCI over time, little is actually known about paediatric SCI in Canada. Using electronic health data from British Columbia and Ontario and health analytics, my proposed research aims to address existing SCI knowledge gaps by 1) developing national case definitions for traumatic and non-traumatic paediatric SCI, 2) estimating the number of Canadian children living with SCI, and 3) increasing understanding of long-term health outcomes and healthcare utilization among children with SCI. Findings from this research will, for the first time, describe paediatric SCI in Canada, identify paediatric populations most at risk of SCI, and identify opportunities to improve paediatric SCI care in British Columbia and across Canada.

Non-invasive Neuroprosthesis for Cardiovascular Recovery Following Spinal Cord Injury

Spinal cord injury (SCI) not just causes paralysis but also more devastating issues such as impaired blood pressure (BP) and heart rate regulation, which are among the leading causes of illness and death among this population. The individuals with SCI above the mid-thoracic level commonly suffer from highly labile BP that rapidly reaches alarmingly high and low levels within the same day. These extreme BP fluctuations often result in seizures, ruptured brain blood vessels and even death. Hence it is not surprising that the individuals with SCI rank improving heart and blood vessel function among the highest priorities for recovery, even higher than regaining the ability to walk again.

The goal of this proposal is to test the potential of non-invasive spinal cord stimulation (delivered through skin) to promote blood pressure control in a rat model of SCI. Our laboratory's pilot experiments have already demonstrated that non-invasive stimulation is feasible and effective in humans with SCI. Present proposal will allow us to thoroughly understand the underlying mechanisms and enable widespread clinical use of spinal cord stimulation in improving quality of life of individuals with SCI.

Detecting neuroplasticity after spinal cord injury: Implications for neuropathic pain

Current interventions for neuropathic pain after spinal cord injury (SCI) have proven largely ineffective, an unfavorable outcome that can be partly attributed to poor understanding of mechanisms.

Through his research program, Dr. Kramer aims to shed light on this problem, focusing specifically on the hypothesis that changes in supraspinal (above the spine) structures contribute to neuropathic pain symptoms (e.g., burning sensation in the legs). In experiments using functional magnetic resonance imaging (MRI) and electroencephalography, a technique for measuring electrical activity in the brain, the brain activities following afferent stimulation in individuals with SCI will be investigated.

In an initial experiment, Dr. Kramer will explore how descending control of nociception, the neural processes of encoding and processing noxious stimuli, is affected by SCI. This will be done using behavioral manipulations to control awareness to noxious stimuli (e.g. placebo-analgesia, the inability to feel pain).

In the second experiment, Dr. Kramer will build on preliminary results, which indicate that neuropathic pain is associated with prominent changes in cortical functioning in brain areas involved in processing noxious stimuli. Beyond cortical functioning, he will also examine the role of plasticity in the brainstem in the maintenance of neuropathic pain.

In a final experiment, Dr. Kramer will delve further into the role of cortical and brainstem plasticity, determining the time course for when these changes occur. In proposed imaging experiments, the extent by which structural changes in the central nervous system accompany sensory deficits will be examined using quantitative anatomical MRI techniques.

As part of Dr. Kramer’s ongoing research program, quantitative approaches to objectively assess sensory function will continue to be developed. The focus of this work will be on validating novel neurophysiological and neuroimaging techniques to examine discrete elements of sensory impairments. Additionally, Dr. Kramer will continue to investigate the inter-relationship between neuropathic pain, other secondary complications (e.g., cardiovascular disease), and neurological recovery by analyzing large epidemiological SCI databases.

Overall, the research program will provide a clearer picture of the impact of neuropathic pain on neurological function, methods to improve objective measurement, and will enable implementation of novel interventions aimed at improving outcomes and quality of life for people with SCI.

Cardiac responses to spinal cord injury and exercise

The prognosis for the 2.5 million North Americans living with spinal cord injury (SCI) is poor. These wheelchair bound individuals are subjected to a number of physical, social, and environmental barriers that compound paralysis and limit daily physical activity. The five-fold increase in risk for heart disease reduces life-expectancy and costs the North American healthcare system $3 billion per annum.

Heart disease is the number one cause of illness and death in the SCI population. On a daily basis, these individuals are tasked with managing abnormal blood pressure control, fatigue, and a host of other bowel and bladder problems. Chronic management of these ‘secondary’ conditions can be poor, owing primarily to a lack of understanding of the underlying mechanisms. In able-bodied individuals, regular physical activity has multiple cardiovascular benefits. Although numerous attempts have been made to engage SCI individuals in regular physical activity, there is limited information available on the cardiovascular benefits of exercise in SCI individuals.

The primary aim of this research project is to investigate the effects of daily physical activity and structured exercise on heart function after SCI.

To improve our understanding of how the heart changes after SCI and the effectiveness of exercise, Dr. West will conduct simultaneous studies in rodents and humans with SCI. The use of a clinically relevant rodent model of SCI will allow Dr. West to answer fundamental questions about cardiac structure and function, and what mechanisms are responsible for the changes that occur after SCI and exercise. The findings will then be translated through conducting assessments of the heart in individuals with SCI.

This project is unique as it will be the first to use ultrasound to make identical measures of heart function in both rodents and humans. Additionally, Dr. West will be able to conduct direct assessments of heart function in the rodent model and follow this up with a detailed examination of the structure of the heart. Finally, he will conduct novel experiments into the effect of lower-limb passive cycling in rodents with SCI and follow this up by assessing how the heart responds to a novel passive leg energetic arm exercise intervention in humans.

Results from this study will yield vital information that can be used to assist in the rehabilitation and management of individuals with SCI.

Brain strain: Effect of autonomic dysreflexia on cerebral blood flow and cognition

Spinal cord injury (SCI) is a devastating chronic condition resulting not only in paralysis but severe autonomic cardiovascular dysfunction. In fact, cardiovascular disease is the leading cause of death in those living with SCI. Autonomic dysreflexia (AD) is a life-threatening condition characterized by episodes of extreme hypertension accompanied by pounding headaches, confusion, seizures, strokes and even death. Despite the high incidence of AD in individuals with cervical or high thoracic SCI and the negative impact this condition has on on the brain, there has been no prior studies examining the relationship between AD and cognition or cerebral blood flow.

Dr. Phillips’ research comprehensively examines cerebral blood flow during progressive AD and relates chronic AD severity to cognitive function. The vast majority of men with SCI experience sexual dysfunction and difficulty with ejaculation. Vibrostimulation is a standard medical procedure that helps with obtaining sperm for the purpose of family-planning. However, this procedure elicits AD in 96 percent of individuals with SCI above T6 and requires careful monitoring. Nonetheless, vibrostimulation offers a unique and ideal model through which it is possible to study the influence of AD on a number of cerebrovascular parameters.

As pilot data for this proposal, Dr. Phillips recorded spontaneously occurring AD bouts in individuals with SCI. In Project 1, Dr. Phillips will examine and measure cerebral blood flow during AD (induced by vibrostimulation) using Transcranial Doppler tests in the middle and posterior cerebral arteries, as well as a newly-developed volumetric technique using duplex ultrasound of the internal carotid and vertebral arteries. In Project 2, Dr. Phillips will examine the relationship between severity of AD (from 24 hour blood pressure monitoring) and cognitive function in SCI.

Ultimately, Dr. Phillips’ study will greatly contribute to the understanding of the cerebrovascular and cognitive effects of AD.