Quantifying navigational impairments in preclinical Alzheimer’s disease

Our brain contains a ‘cognitive map’ of the external world that helps us navigate, and encode/retrieve memories. Dementias such as Alzheimer’s Disease (AD) degenerate these regions, causing well-known memory impairments and much less well-understood navigational impairments. My research program seeks to quantify how navigation is impacted in early AD in rodents and humans.

Young and older human participants will navigate a virtual reality maze. We will quantify how their errors in positioning and navigating scale when the complexity of the task is increased. We will perform similar experiments in rats navigating a physical maze, where we can additionally record neural activity. We will then extend the task to participants diagnosed with preclinical AD, and rodent models of AD. We will characterize the behavioural and neural correlates of early progression of AD, with the goal of finding a metric that is predictive of AD-induced cognitive impairment, and its underlying neural mechanisms.

Over 60,000 British Columbians currently live with dementia. A non-invasive and affordable test such as this will allow clinicians to perform early diagnosis, and start approaches that reduce symptoms and improve quality of life.

Mucus-directed therapeutics to prevent and treat chronic microbiota-dependent diseases of the gut

The colon is teeming with life, not just due to our own cells, but also due to a rich and diverse community of microbes. Remarkably, this community is a virtual organ, helping to digest food and fight inflammation. Unfortunately, this “organ” can malfunction and cause chronic diseases like inflammatory bowel disease (IBD), which affects thousands of Canadians. How to promote the benefits and prevent the harmful activities of our microbiota is a central question. One major factor is gut mucus, a sugar-rich gel-like layer that surrounds the microbiota to act as a barrier to prevent their invasion. This mucus layer is defective in IBD. The objective of my research is to develop new ways to capture the protective power of human mucus to prevent and cure IBD. To do this I will use a new approach my lab developed to extract and purify human mucus to test its protective abilities in mouse models of IBD. We will also learn how microbes control mucus production so we can target these pathways in patients. Last we will use human colon cells to generate a “mucus factory” that can produce mucus with enhanced protective properties. The results of this research will illuminate new paths to restore healthy host-bacteria relationships in IBD.

Integrating functional glycomics and genomic screening to reveal new targets for cancer immunotherapy

All of the cells in our body are coated with a dense layer of sugar molecules. Cells in our immune system constantly “taste” these sugars. Some types of sugar taste good to our immune system, signaling that our cells are healthy. Other sugars (like those attached to invading bacteria, viruses or cancer cells) taste bad to our immune cells, triggering them to activate and try to protect us from disease. Sometimes, our own cells can become altered in ways that lead them to produce abnormal types of sugar molecules on their surface. When this happens, it can allow cancer cells to evade detection and destruction by the immune system. Our group applies powerful genomics technologies to better understand how human cells generate these immune-regulatory carbohydrates. This information allows us to predict when cell-surface sugars may become chemically altered and identify specific molecules that can be targeted for manipulating immune activity. The insights generated from our research directly impact the design of new immune-targeted cancer therapies.

Beyond Sex and gender: advancing a biosocial understanding of affective processes.

Affective processes such as stress and emotion are at the heart of how we understand ourselves and interact with the world around us. Human and animal research supports the role of sex and gender-related factors in affective processes; however, the neurobiological mechanisms that influence affective processing remain unknown. While sex and gender are traditionally defined, respectively and separately, as biological and social dimensions of a person, alternative approaches rooted in interdisciplinary research rather conceptualize our biologies as inseparable from our social experiences. The proposed program of research aims to explore how an interdisciplinary gender/sex approach (as opposed to the distinct gender and sex approach) influence the neurobehavioural processes of stress and emotion. This research will expand our understanding of how context shapes biological and subjective experiences of stress and emotion and advance the development of integrated theories that will shape the future of gender/sex research.

Evaluating microstructural changes in multiple sclerosis with magnetic resonance imaging

Multiple Sclerosis (MS) can be difficult to detect, diagnose, and treat. It is often initially assessed by excluding other potential disorders and diseases as well as (where possible) a confirmatory magnetic resonance imaging (MRI) exam. While MRI can confirm the presence of MS lesions in the brain, the exam is of limited use in explaining or predicting symptoms or prognosis.

Following the initial diagnosis, there are a number of medications that can be used to attempt delay the progression of the disease. However, it is challenging to assess the efficacy of a particular course of treatment unless disease progression is detected through the accumulation of additional disability or a follow-up MRI exam confirms the presence of new lesions.

There may be other changes to the brain which may help scientists and physicians to understand how and why MS progresses and identify how well medications are working for a particular individual. Thus, the objective of this work is to leverage the power of a safe, non-invasive, imaging tool (MRI) to detect and evaluation changes to the brain that can help us better treat patients with MS.

Errors, Uncertainties, and Ambiguities in Wearable Health Monitoring Systems

Healthcare and diagnostics have recently undergone a paradigm shift with a greater focus on remote health monitoring through wearable technologies. Advances in miniaturized electronics, wireless communications, and big data analytics are all converging in this space to take health monitoring out of the clinic and into the home. However, while the exponential increase in wearable technologies is driving excitement in this field, such technologies have found limited success in clinical integration. While consumers might find a plethora of smart gadgets from watches to rings that can track activity and heart rate, little of this information is getting utilized by clinicians. This is in part due to the lack of transparency and perceived inaccuracy of wearable monitoring systems. We will address this limitation by characterizing errors in measured real-world health signals, accounting for errors in user-device interactions, and capturing uncertainties and ambiguities in decisions that will allow wearable sensors and underlying machine learning algorithms to provide more contextual and nuanced information for clinicians. This will help clinicians decide when and how to apply wearable data to clinical decisions.

Targeting neuronal maturation to promote axon regeneration after spinal cord injury

Spinal cord injury leads to permanent and severe paralysis and loss of sensation. The principal reason for this is that nerve cells connecting the brain with the rest of the body lose the capacity to regenerate their processes (axons) as they mature during development. Despite decades of progress, no regenerative therapy for the injured spinal cord is available today, making a regenerative treatment for spinal cord injury a major unmet need of the British Columbia healthcare system. In this project, we will focus on the fundamental processes through which maturation suppresses axon regeneration. We have discovered a molecular switch that is turned off in mature neurons and that we hypothesize is critical for nerve cells to regrow axons. We will study how this molecular switch is turned off during maturation, the processes that it controls to enable growth and test whether re-activating it in mature neurons can promote regeneration and functional improvements following spinal cord injury. Collectively, this work will provide critical insight into why mature nerve cells fail to regenerate. We anticipate that this work will be a major steppingstone towards the development of a treatment that regenerates the injured human spinal cord.

Development of Metabolomics to Interrogate the Effects of Maternal Sugar Overconsumption on Pregnant Rats and Their Offspring

Sugars such as sucrose (table sugar) are extremely common in the diet, in Canada and across the world. The World Health Organization advises that added sugars should make up 5% or less of daily calories for adults, and even less for children under 2 years. However, in Canada, adults and children often greatly exceed these recommendations. Of particular concern, added sugars during early development might have major and long-lasting effects on hormones, neural circuits, and behaviour. Our work is to develop sensitive and robust metabolomics technology to identify the key sugar products and other chemicals that play a key role in this biological process. This work allows us to understand the molecular basis between sugar intake and the long-lasting effects on adult offspring. The results will have important implications for the health of Canadians because very little is known about how mother’s sugar intake affects the baby health and diseases.

The oxygen cascade as a therapeutic target in humans with hypoxic-ischemic brain injury

During a cardiac arrest the heart stops beating and blood flow to the brain stops, starving the brain of oxygen and causing a brain injury. In resuscitated patients whose heart starts beating again, this brain injury is the number one cause of death. As no therapies are available to treat this brain injury, my research will determine ways to improve the treatment of post-cardiac arrest patients with a brain injury. My research will use measurement probes placed directly in brain tissue as well as the analysis of blood entering and leaving the brain in humans to: 1) determine how to restore optimal oxygen levels in the brain; 2) develop tests to identify patient specific factors underlying low brain oxygen levels that can then help guide personalized patient care; and 3) investigate the molecular mechanisms of this brain injury. This work will be foundational to the development of new therapies to treat brain injuries caused by low oxygen levels in the brain. By determining widely implementable techniques to identify how oxygen delivery is impaired at the bedside, we will be able to tailor care in central and rural settings within British Columbia and provide patients with the specific treatments that work best for them.

Advanced multi-functional in vivo retinal imaging for ocular oncology

Ophthalmic imaging plays a crucial role in the evaluation, follow-up, and treatment decision-making in ocular oncology. This critical role is even more prominent when dealing with the early-stage choroidal melanoma or amelanotic tumor patients, in which diagnostic uncertainty is especially prevalent. This is due to the significant overlap in the clinical and imaging findings of benign and malignant choroidal tumors. Current imaging modalities are not helpful in reliably differentiating the malignant features in suspicious choroidal lesions and often require long-term serial follow-up that places a significant burden on patients and providers. Recent studies have shown that melanin alternation in the choroid is correlated to the malignancy and metastasis potential in choroidal tumor patients. The main goal of my research is to develop a novel high-resolution, molecular-specific clinical ophthalmic imaging system to visualize and quantify the melanin contents in choroidal tumor. This research outcome will provide important diagnostic clues in the evaluation of choroidal tumors, facilitating early non-invasive identification of high-risk features of malignancy.