Intellectual disability (ID) is a life-long affliction that impairs the cognitive functioning and adaptive behavior of affected individuals. About two to three percent of people worldwide suffer from ID. ID is mostly caused by irregularities in the DNA of an individual and is the most common reason for genetic testing. There are thousands of different mutations that we now know can cause ID. Diagnosis is necessary for accurate and effective genetic counselling, however deciphering the underlying genetic component remains a challenge.
The emergence of next-generation sequencing technologies, notably whole-genome sequencing (WGS), has empowered the identification of genetic cause in more than half of all patients with severe ID. WGS allows scanning of the entire genome of an individual for abnormalities in DNA sequence. The number of accurate diagnoses are three to four times higher than what is achievable with current methods. The current major limitation is that WGS fails to detect certain types of mutations.
Dr. Rajan Babu’s research aims to improve the clinical effectiveness of WGS by expanding its detection abilities to include all ID-causing pathogenic mutations, including those that aren’t currently being identified. She will employ an advanced WGS technology and analyze the generated data using three well-optimized bioinformatics pipelines, enhancing the diagnostic sensitivity of WGS.
The results of this research will be incorporated in the standard clinical diagnostic evaluation of patients with ID to promote earlier and definitive diagnosis, and enable optimal clinical care and counselling of affected patients and their families. All patients with clinically actionable finding will be offered genetic counselling and consultation with appropriate medical specialists. Ultimately, Dr. Rajan Babu’s research could facilitate discovery of novel genetic aberrations and refine our understanding of the genes and the biological mechanisms involved in ID as well as reveal new potential targets for therapeutic intervention.
Vision loss from age-related macular degeneration (AMD) and other retinal degeneration diseases is due to the loss of the light sensitive photoreceptor cells in the eye. This is often secondary to dysfunction of the retinal pigment epithelium (RPE).
The photoreceptor and RPE cells are arranged in a characteristic mosaic. The mosaic is an accurate clue to how healthy these layers are. However, attempts to visualize these mosaics have been so far unsuccessful, despite technological advancements in conventional ophthalmic imaging.
Dr. Ju will develop a novel clinical ophthalmic imaging system to visualize and quantify the changes of the structure and function of photoreceptor and RPE cells in humans. The results of this research will provide a clearer understanding of the pathological processes of AMD, which will help clinicians establish more reliable clinical treatment options.
Children with attention-deficit/hyperactivity disorder (ADHD) have trouble sustaining attention and may also display excessive hyperactivity and impulsivity. A major day-to-day impairment for children with ADHD is in their social relationships with peers. In this area, children with ADHD frequently struggle, and have trouble making and keeping friends as a result. It is important to address these issues early, as social problems increase children’s risk for many negative outcomes including academic failure, aggression and delinquency, substance abuse, and depression and suicide.
Research suggests that difficulties with executive functions (e.g., attention, self-control, working memory, organization and planning) are a key part of ADHD. However, it is not yet clear how executive functioning difficulties may affect the problems children with ADHD face in their daily life, such as peer relationships.
Dr. Hudec will explore how executive functions relate to social skills and the ability to make and keep friends in children with ADHD. This will lead to a better understanding of the social problems affecting children with ADHD.
Importantly, symptoms of ADHD frequently occur within families, so parents of children with ADHD are more likely to experience ADHD themselves, and to be at risk for poor executive functioning themselves. Dr. Hudec will also examine how parental executive functioning may affect parents’ ability to implement behavioural interventions.
Understanding how executive functioning in both children and adults affects children’s social problems may help improve available clinical treatments for children with ADHD and will guide development of therapeutic activities that can be adapted to parents’ strengths and weaknesses. Dr. Hudec’s findings will be shared through family-based interventions and community-based education sessions, as well as professional presentations and publications that will inform practice by researchers and clinicians.
The complex microbial ecosystem inhabiting the distal human gut, known as the gut microbiota, is inextricably linked to human health, playing central roles in maintaining host immunity, safeguarding the host against pathogens, and extracting energy from the otherwise indigestible complex carbohydrates found in dietary fibre.
Dysbiosis, an imbalance in the gut microbiota, is linked to a range of diseases, including inflammatory bowel diseases, metabolic syndrome, and Type 2 Diabetes. A growing body of evidence supports a role for microbial therapeutics, such as commercially available probiotics, in mitigating the effects of some dysbiosis-associated conditions. However, the implementation of novel, customizable therapeutics depends on the establishment of a comprehensive repository of species with known energetic requirements and ecological behaviours.
Currently we lack atomic-resolution insight into the molecular machinery required for complex carbohydrate utilization by key gut symbionts. Understanding this machinery is critical to understanding the role of carbohydrate utilization in shaping microbial communities in the human gut.
Dr. Grondin will employ structural biology in a systems-based approach, incorporating complimentary bacterial genetics and carbohydrate biochemistry to determine the atomic structures of transport protein machinery in complex with the related substrates. Comparative structure-function studies of carbohydrate-transporters, including measuring transport specificity and kinetics across substrate type and bacterial phylogeny, will delineate the role of individual complexes in fuelling microbial ecosystems. This research will provide detailed insights into the molecular mechanisms associated with the selective recognition, transport and metabolism of complex carbohydrates by the human gut microbiota. The results of will inform the development of therapeutics to address growing health concerns associated with microbiotal imbalance, such as inflammatory bowel diseases, metabolic syndrome, and Type 2 Diabetes.
Spinal cord injury (SCI) resulting from traumatic accidents is one of the most debilitating chronic conditions. In addition to the toll on quality of life, lifetime health care expenditures for these patients are among the most expensive of any medical condition, since many injuries occur in young patients who live with SCI for decades. SCI also comes with steep indirect costs, including morbidity due to chronic complications.
In individuals with SCI, bladder dysfunction and episodes of high blood pressure are two chronic conditions that present as significant clinical problems. Bladder dysfunction is commonly associated with a sudden, life threatening increase in blood pressure known as autonomic dysreflexia (AD). This episodic hypertension cannot be addressed with typical treatments, and if misdiagnosed or poorly managed can lead to myocardial infarction, stroke, and even death. Bladder dysfunctions and irritation such as a urinary tract infection are leading triggers for AD.
It is suspected that chronic exposure to AD episodes results in cerebrovascular damage in those with SCI. Chronically elevated blood pressure negatively impacts the brain and is specifically associated with cerebrovascular decline, altered brain morphology, cognitive dysfunctions and stroke in able-bodied individuals. However, identical pathologies are present in those with SCI.
Dr. Walter will investigate whether treating bladder dysfunction in patients with SCI will decrease possible triggers for episodes of AD, ameliorate its symptoms and consequently reduce chronic cardiovascular complications. Reducing the chronic cardio- and cerebrovascular complications of SCI would dramatically improve the health and wellbeing of patients with SCI and positively impact health care costs.
One in eight men in Canada will be diagnosed with prostate cancer in their lifetime. Despite the availability of surgical, radiological and drug treatment options, many patients develop castration resistant prostate cancer (CRPC), an incurable disease which is especially resistant to drugs. In its most lethal form, drug resistant CRPC behaves like a neuroendocrine cancer, which is completely unresponsive to traditional prostate cancer therapies.
In his model of drug resistant CRPC, Dr. Munuganti has identified a molecular pathway that appears to be essential for prostate cancer to take on neuroendocrine features. A key protein in this pathway, BRN2, is high in patients with neuroendocrine prostate cancer and is critical for neuroendocrine tumour growth in a laboratory model. BRN2 expression also plays a critical role in other neuroendocrine cancers such as small cell lung cancer and Ewing sarcoma. There is an urgent need to develop drugs that have the ability to inhibit the function of BRN2 for the treatment of patients with deadly neuroendocrine tumors.
Using high-powered and intelligently designed computer models, Dr. Munuganti has developed drug prototypes that have the ability to prevent BRN2 from supporting neuroendocrine cancer cell growth in our laboratory models. Dr. Munuganti’s study will fine-tune the drug-like properties of the leading BRN2 inhibitors and test them in biological models of neuroendocrine cancers. The results of this research could lead to the development of new therapies capable of reducing or slowing the growth of lethal neuroendocrine cancers, substantially improving patient survival.
Findings will be presented at conferences and seminars such as AACR Annual Meetings and the ASCO Annual Meeting, providing an opportunity to exchange ideas with other researchers and clinicians in the field and opening up possible collaborations. The ultimate goal of this study will be to commercialize a BRN2 inhibitor for patients suffering from no-cure neuroendocrine tumours.
Recent debates about palliative end-of-life (EOL) care and legalized assisted dying have stimulated new questions about EOL care for those living with dementia. However, when discussing preferences for EOL care, individuals with dementia are often excluded from the decision-making process, leaving decision making to family members and/or care providers.
With growing numbers of people living with dementia, it is imperative to understand what they envision for their EOL care. While some research suggests they are able to discuss their preferences for care, there is a significant gap in understanding what people with dementia envision for their own EOL care and how they and their family members share in the decision-making process.
Utilizing a critical narrative approach that employs in-depth interviews, visioning workshops, visual arts and storytelling, Dr. Puurveen will examine the EOL preferences and shared decision-making processes of people living with dementia and their family members. Her study will explore:
- How people with dementia and their family engage in shared EOL decision-making.
- The kinds of decisions that they make regarding future care.
- How the age, gender, race, and relationships of individuals with dementia and their families, as well as larger socio-political factors such as legalized assisted dying, influence EOL decision-making.
- What people with dementia identify as an important message about EOL care that can be shared with the public.
To provide an opportunity for conversation beyond those immediately involved in the research, a public art exhibition will be held at a local gallery that invites members of the public, care providers and policy makers to view the art created at the visioning workshops and reflect upon living well with dementia to the end of life.
Dr. Puurveen’s findings will generate practice and policy recommendations for improving EOL decision-making (e.g., advance care planning), that will in turn help improve the quality of care of individuals with dementia and their quality of life at the EOL.
Heart failure (HF) is a progressive condition wherein the heart is unable to fill its chambers and/or pump sufficient blood into the arteries. While there are many causes of HF, it usually presents in two major forms: HF with preserved ejection fraction (HFpEF; ‘stiff’ heart), and HF with reduced ejection fraction (HFrEF; ‘baggy’ or ‘weak’ heart).
A key challenge in HF diagnosis is that, while the causes of HFpEF and HFrEF differ, their clinical presentation is often the same. As a routine echocardiogram in HFpEF can appear normal, the diagnosis can be overlooked and delayed. In clinical practice, the diagnosis of HF is often made late, at which time evidence-based treatments or other lifestyle strategies may have less benefit for those with HFrEF. At the same time, many HFpEF patients are being treated with drugs that provide no proven benefit.
Dr. Singh will investigate novel, non-invasive diagnostic approaches that can identify patients with HFpEF versus HFrEF at an early stage of disease. The results of this research will include innovative methods for data integration and biomarker discovery, which will improve biological insights into the mechanisms of HF. Identifying the form of HF earlier on will allow clinicians to develop and tailor diagnostic and therapeutic approaches, and use a firm diagnosis as a tool to encourage lifestyle changes.
Diagnosis of HFpEF versus HFrEF will ensure that the most appropriate additional tests and treatments can be provided for each patient in a timely fashion, improving disease management and patient quality of life.
With every heartbeat, one quarter of all the blood in the body flows through the brain. This activity is essential for the health of neurons in the brain throughout life. Although scientists realize that understanding how to keep blood vessels in the brain healthy may offer new ways to treat brain disorders including Alzheimer’s Disease, a big challenge facing this area of inquiry is the lack of methods available to study the brain’s blood vessels outside of an animal model, which do not always mimic the human condition closely enough to provide answers that help to develop effective treatments for brain disorders.
Dr. Robert has to date made considerable progress in being able to grow functional, three-dimensional and human-derived cerebral blood vessels in vitro using tissue engineering technology, and has used these vessels to analyze the accumulation of beta-amyloid peptide, which is a pathological hallmark of Alzheimer’s disease.
The primary goal of Dr. Robert’s research, in collaboration with the Canadian Consortium of Neurodegeneration and Aging , is to use this novel platform to better understand how blood and brain lipoproteins affect human cerebral vessel health.
Although lipoproteins are traditionally known for their roles in carrying fats through aqueous body fluids, recent research has revealed that lipoproteins also influence inflammatory pathways and cellular signalling. Importantly, the composition of human lipoproteins are very different than their murine counterparts, and so far existing neurodegenerative disease mouse models have not been able to accurately model these differences.
Dr. Robert’s innovative platform allows for mechanistic studies in a fully human experimental system. As such, the major translational plan for this research will be to disseminate findings to the academic and clinical communities through publication and presentations. As Dr. Robert’s methods use many technologies already established in cardiovascular medicine, the results will also be of significant interest to the medical and research communities and drive accelerated progress toward understanding the contribution of cerebrovascular dysfunction to dementia.
In Canada, a striking 13% of children (~500,000) have asthma. It is the leading cause of absenteeism from school, and accounts for more than 30% of Canadian health care billings for children. Asthma is also the leading cause of hospital admissions in both children and the general Canadian population. Given that asthma typically begins in childhood and lasts throughout life, the high prevalence, combined with significant related morbidity, make asthma the most common and burdensome chronic non-communicable disease affecting young Canadians.
Asthma is a complex disease dependent on the interactions of genetic predisposition with environmental factors including physical, microbial, and social environments. The Canadian Healthy Longitudinal Development (CHlLD), a cohort study funded by CIHR, has recruited over 3,500 pregnant mothers to collect such environmental and biological data from pregnancy up to age five in four Canadian cities: Vancouver, Edmonton, Toronto and Winnipeg. The proposed project will use biological and environmental data from the CHILD cohort and will focus on traffic-related air pollution and natural spaces. These two modifiable environmental exposures have been shown to be associated with asthma exacerbation.
The novelty of this research lies in the study of joint exposures and their interactions over time; their impact likely depends not only on individual genetic profiles, but also on the critical timing of exposure. Early life period, including in utero, is a critical influence on health in later life. Likewise, changes in gene function in relation to environmental influences provide evidence to explain how and why asthma and allergies exist and progress.
Dr. Sbihi’s research will examine how these changes, called epigenetic modifications, are affected by the early-life environmental exposures, including the body’s microbial milieu. By examining how the environmental exposures (traffic air pollutants, natural spaces, gut microbes) impact DNA methylation and consequently how these epigenetics modifications lead to asthma, we will be able to better understand the mechanisms of asthma development and subsequently provide better targeted prevention measures.
