Development of a flow cytometry assay for accurate and selective measurement of lysosomal GBA1 activity in PBMC

Recently, loss-of-function mutations of the GBA1 gene, which encodes glucocerebrosidase (GCase), have been characterized as a major genetic risk for Parkinson’s disease (PD). Patients carrying these mutations have a much higher incidence of PD, earlier onset, and more severe disease. 

These data strongly suggest that GCase activity may be useful for early diagnosis as well as monitoring the progression of PD. Dr. Gros will build on her previous work describing a substrate that specifically measures GCase activity both in vitro and in neuronal cells in microscopy. This research will lead into a proof-of-concept clinical study, using a flow cytometry assay to establish correlations between the progression of PD, GBA1 mutant status and GCase activity.

The results of this study will lead to the development of a new assay for clinical studies that will benefit Parkinson’s patients and deepen our overall understanding of the disease.

 

Studying genetic mechanisms of treatment resistance in non-Hodgkin lymphomas

Dr. Morin's research program will develop and apply laboratory and computational genomic methodologies that use DNA sequencing and other sensitive platforms to study the drivers of tumour onset, progression and treatment resistance in solid cancers in order to understand the somatic drivers of non-Hodgkin lymphomas (NHLs). Using massively parallel (next-generation) DNA and RNA sequencing, Dr. Morin will be able to identify somatic alterations and gene expression signatures in tumour tissue and liquid biopsies (circulating tumour DNA). To properly study such large data sets, he will utilize cutting-edge bioinformatics techniques and develop novel analytical approaches and pipelines that will allow leverage of unique sample processing techniques and applications.

Moving forward, this research will investigate aggressive subtypes of NHL including patients who typically fail standard-of-care treatments. Dr. Morin will rely on features of this malignancy such as high somatic point mutation rate, a well established list of known lymphoma-related genes, and the presence of clonal immunoglobulin rearrangements to develop assays to study the genetics of specimens from NHL patients in various ways. These include deep sequencing using a novel molecular barcoding system and digital PCR-based methods. He will continue to push the limits of sequencing technology by applying deep sequencing and whole exome sequencing to circulating tumour DNA. Under this research program, he will also continue to use a variety of laboratory and computational approaches to understand the clonal structure of NHLs, especially in the context of serial samples collected over the course of disease progression and after treatment failure or relapse. 

Dr. Morin's lab, along with the BC Cancer Agency, plan to pursue options to commercialize these strategies so that a broader group of users can use these techniques for research and clinical applications. Some of the research under this program will involve evaluating the performance of novel ctDNA-based methods to study tumour genetics and evaluate treatment responsiveness. This will be conducted in the context of prospective and retrospective samples from multi-centre clinical trials in Canada. This engagement with clinicians and publications describing these trials will help accelerate the adoption of such emerging technologies to the clinic.

Endothelial cell regulation of T cell responses

Organ transplantation is a life-saving procedure for many individuals. Unfortunately, the long-term success of this procedure is compromised by the rejection of the transplanted organ(s) by the recipient's immune system. T cells are specialized cells of the immune system that protect against infections but that recognize and damage transplanted organs. Understanding how T cell responses are controlled will help to develop new methods to increase the long-term and specific acceptance of transplanted organs.

Dr. Jonathan Choy's research is focused on understanding how T cell survival and persistence is regulated and how these processes contribute to organ transplant rejection. By understanding this, Dr. Choy intends to find new ways of controlling the immune response against transplanted organs. Preventing rejection will improve outcomes for the approximately 2,000 Canadians who receive solid organ transplants each year, as well as for the many Canadians who are already living with transplants.

Immunobiosensor-Based Analysis of Antigen-Specific B-Cell and Plasmablast Responses during HIV-1 Infection

The study of the cellular basis of antibody-mediated immunity in infection is an exciting, emerging field of research that has profound implications for our understanding of host-virus interactions, protective immunity and HIV vaccine design. Antibodies are proteins that are produced by plasma cells and bind to molecules on the surface of invading pathogens, flagging them for destruction. Research in the field of HIV/AIDS has shown that antibodies, which neutralize a broad range of HIV isolates in test tubes, also protect animals from HIV-like pathogens, such as simian immunodeficiency virus (SIV). Thus, there has been a concerted effort to design vaccines that elicit broadly neutralizing antibodies targeting HIV. HIV-infected people rarely produce protective antibodies against a broad range of viral variants; this is of great concern to those attempting to produce a vaccine. Currently, there is no way of isolating the blood plasma cells that produce and secrete antibodies against a particular molecule or pathogen (antigen).

Dr. Naveed Gulzar's research involves an innovative approach to identify single, live HIV-specific plasma cells whose secreted antibodies bind proteins associated with HIV. He is working with a multidisciplinary team to develop an immunobiosensor that will allow him to locate single cells that secrete HIV-specific antibodies from thousands of antibody-secreting cells from the blood of HIV-infected people, and to isolate them for subsequent analyses. His goal will be to characterize the antibody response against HIV envelope proteins, and see how these change during the course of infection. The genes encoding these antibodies will be analyzed and their features compared. The results may provide new insights into our understanding of the immune response against HIV infection.

Dr. Gulzar's team includes Dr. Jamie Scott and several different analytical chemistry, physics and engineering research groups at Simon Fraser University and the University of Victoria, along with Cangene, a Canadian industrial partner. They anticipate that by understanding the genetic and cellular features associated with antibodies that neutralize a broad range of viral variants, they will be able to better inform the design of an HIV vaccine that elicits broadly neutralizing antibodies.

The role of emotion regulation in borderline personality disorder and self-injury

Borderline personality disorder (BPD) is among the most complex, misunderstood, and stigmatized mental health problems. It is a serious psychiatric condition characterized by instability in relationships, emotions, identity, and behaviour that often induces intense emotional suffering and places affected individuals at high risk of suicide and self-injury. Approximately 10% of individuals affected by BPD die by suicide, 75% have attempted suicide, and 70-80% self-injure. BPD is also a significant concern for the public health-care system. Patients affected by BPD represent up to 20% of psychiatric inpatients and heavily utilize outpatient and hospital emergency services. In fact, the estimated costs to the health-care system per year for each BPD patient range from US$12,000–$30,000. Self-injury and other problems in BPD appear to be related to problems in the management of emotions, or emotion regulation problems.

Dr. Alexander Chapman’s research aims to better understand and treat BPD and related problems, such as self-injury and suicidal behaviour, by examining the role of emotions in BPD and self-injury. Research in his lab, the Personality and Emotion Research Laboratory, includes a variety of studies aimed at better understanding what causes and maintains BPD and self-injury, as well as studies designed to help us understand how to effectively treat BPD. He is also conducting studies on the risks and protective factors for self-injury.

Dr. Chapman’s short-term goal is to continue to develop his research on BPD in two key areas: (1) the role of emotion regulation in BPD and self-injury, and (2) effective treatments for BPD and NSSI. He has several grants for studies in these areas and hopes to expand this research over the next five years. In the long-term, Dr. Chapman would like to develop an interdisciplinary research, treatment, and education centre focused on BPD, self-injury, and related health problems. Such a centre would be unique in Canada and would have the potential to significantly improve our understanding and treatment of BPD as well as the education and training of junior researchers and professionals.

An examination of internet use for health information among Canadian baby boomers using the 2000 general social survey

The internet is a powerful health promotion tool, and it’s predicted that this technology has the potential to influence the way health information and services are distributed and accessed. Baby boomers (those born 1946-1965) are a prime target for this type of health promotion technology, since they have been exposed to the growth and widespread use of the Internet. Additionally, baby boomers are more concerned about healthy lifestyles and healthy aging than previous generations, are more interested in self-help resources, and are more demanding of good service. While previous research has found a high percentage of internet access and use among older Americans, no surveys have been carried out in the Canadian context. With the proper education and tools, baby boomers can not only delay functional loss, but improve their current health status and prevent the onset of several chronic illnesses and disabilities that begin to appear in mid-life. Providing them with appropriate, targeted resources requires knowledge about current utilization trends, needs, barriers and other concerns that could be hindering them from seeking online information regarding their health. Danielle Sinden is using national data gathered as part of the 2000 General Social Survey to examine trends, types, and levels of access to the Internet. She is also exploring predictors of health information-seeking behaviour, including sex, socioeconomic status, living arrangement/marital status, foreign-born status, region of residence, and perceived barriers and usefulness. Sinden’s research will lay a foundation of knowledge for developing online health promotion strategies targeting modifiable risk factors for baby boomers. Ultimately, this could lead to more favourable long term health outcomes that contribute to healthy aging.

The effect of co-led mutual support groups in long-term care facilities on well-being

The social relationships that residents form within long-term care facilities (LTCF) are believed to buffer them from loneliness and depression to a greater degree than relationships with family and friends outside of facilities. Furthermore, support from friends and social groups has been associated with positive outcomes for older people living with chronic and serious health conditions. Traditional social activities in LTCF are not usually led by residents and are often passive entertainment programs that don’t provide the necessary supportive environment for residents to interact beyond surface social interactions. These activities are not usually grounded in research evidence, and some programs intended to foster resident well-being actually have adverse effects, including the perception among residents that activities offered are “childlike.” Currently, there is a lack of research evidence showing the benefits of specific social activity programs provided to residents in LTCF. One aspect of particular interest is the use of co-led self-support groups, which aim to enhance residents’ sense of belonging, self-development and self-determination. In this format, an activity staff member co-leads the groups with a resident group member, and acts in the role of a facilitator in order to assist with any special needs of the residents. Kristine Theurer is studying the benefits of co-led mutual support groups. Her assessments of resident well-being will be based on measures of sense of belongingness, loneliness, life satisfaction and happiness. From her findings, she will provide recommendations for co-led group formation, number of participants, suggested theme topics and supportive materials. Ultimately, her work will help LTCF provide appropriate evidence-based programming that supports residents to achieve a better quality of life.

Making Outreach Matter: Exploring Interventions and Decision-Making for Two Intravenous Drug User Populations in Vancouver’s Downtown Eastside

Within the intravenous drug user (IDU) population of Vancouver’s Downtown Eastside (DTES), female commercial sex workers and Aboriginal women are overrepresented. These two groups are especially vulnerable to unique sets of health and social challenges that may be related to their substance dependency, including increased susceptibility to sexually transmitted infections, physical violence, psychological trauma and malnutrition. Their social challenges can include increased contact with law enforcement, lower education, unemployment and inability to access community support. The needs of these two groups both intersect and diverge based on a series of factors. There are currently numerous services and interventions that target intravenous drug using women, including emergency mental health counselling, addictions treatment and recovery, harm reduction (both for IDU and commercial sex work) and general support groups. However, the rates of use of these services by commercial sex workers and Aboriginal women are relatively low. This suggests that many women either choose not to or cannot make use of the available health services and interventions. In order for these interventions to effectively help these two groups of women in coping with deeply interconnected health and social challenges, these factors must be investigated, addressed and understood within a complex matrix. Ashley White is conducting an in-depth study to explore the characteristics, perceptions of health services, and needs of commercial sex workers and Aboriginal women practising intravenous drug use. Her findings will provide essential insight into potential ways that health planners can offer accessible services that better meet the requirements of these women.

Dissection of O-glycosylation of nuclear and cytoplasmic proteins

The recent decoding of the human genome surprisingly revealed that humans possess a relatively small number of genes. Yet despite this apparently small number, we are rather complex beings. Genes are a special code that can be read out to form proteins, which are responsible for the vast majority of biochemical process within our bodies. This apparent inconsistency between the number of genes and the complexity of humans can be, in part, accounted for by various ‘post-translational modifications’ of human proteins. These types of modification are often additional molecule groups that are added onto certain positions in the protein and can change its activity. Dr. Tracey Gloster is interested in a modification where there is addition and removal of a sugar called ‘N-acetylglucosamine’. Disruptions to this modification are implicated in conditions such as diabetes, cancer and neurodegenerative diseases. The enzyme responsible for adding the N-acetylglucosamine modifies a large number of completely different target proteins. Little is known about how the enzyme recognizes its targets and modifies them at the correct position to ensure they carry out their proper function. Gloster is investigating a specific domain on this enzyme that could hold the answer. There are multiple sites on this interacting domain which she believes each recognize different sets of target proteins. By finding proteins that are modified by this protein and determining the exact region of the target protein that binds to the enzyme, it may be possible to block the enzyme’s action. This could open up new therapeutic approaches in the treatment of diabetes and other diseases.

Yeast oxysterol binding proteins and the cholesterol dependent regulation of Rho-GTPase mediated polarized cell growth

Heart disease is the leading cause of death for Canadians. More than one million Canadians currently live with this chronic disease and every year, more than 81,000 die. A major contributor to heart disease is cholesterol. Ironically, even though too much cholesterol is bad for our health, it cannot be completely removed from our bodies because it is essential for human life. Controlling dietary cholesterol is not always enough to reduce cholesterol levels in the body since our cells can also produce their own cholesterol. Loss of cholesterol regulation in our bodies not only leads to heart disease, it is also causes problems inside cells that can lead to other disease states. In fact, recent studies showed that the use of cholesterol-reducing drugs not only lowered cholesterol, they also decreased the incidence of breast cancer in Canadian women by 74 per cent. Recently, a group of cholesterol-binding proteins were identified and have been shown to mediate many of the functions linked to cholesterol. Gabriel Alfaro is using microscopy, biochemistry, and genetics to determine the mechanisms underlying how these proteins affect cholesterol regulation and mediate cellular functions. His research uses baker’s yeast as a model system, since the regulation of cholesterol in yeast is similar to its regulation in humans. Gabriel Alfaro’s research will enhance our understanding of the role cholesterol plays in the cell, and potentially point to new drug targets that could have fewer side effects relative to the current broad spectrum cholesterol inhibitors. Furthermore, his research will help elucidate the mechanism underlying cholesterol-related diseases