Research Location: Simon Fraser University

An advanced wearable robotic exoskeleton for assisting people with lower limb disabilities

Human locomotion is influenced by many factors, including neuromuscular and joint disorders that affect the functionality of joints and can cause partial or complete paralysis. Reduced mobility is estimated to affect over 1.5 million people in the United States alone. Many individuals require mobility assistive technologies to keep up with their daily life, and the demand for these devices increases with age.

A wearable robotic exoskeleton is an external structural mechanism with joints and links corresponding to those of a human body. It is synchronized with the motion of a human body to enhance or support natural body movements. The exoskeleton transmits torques through links to the human joints and augments human strength.

Dr. Arzanpour has developed a novel wearable robotic exoskeleton for assisting people with lower limb disabilities, such as spinal cord injury patients. The robot is highly versatile and capable of guiding the lower limb joints to perform all normal and complex movements. The technology is light, modular, portable, programmable and relatively inexpensive, and is particularly innovative in its versatile hip, knee and ankle joint mechanism, such that the normal range of motion of the natural joints is preserved.

So far, a proof-of-concept prototype of the proposed lower limb exoskeleton has been fabricated and successfully tested on an anthropomorphic test dummy. With further progress this technology could help people with lower limb disabilities to walk again and greatly improve their quality of life.

Neuromodulation research program for youth addiction and mental health

Each year, approximately 1 in 5 Canadians experiences a mental health or addiction problem. Young people aged 15 to 24 are more likely to experience mental illness and substance use than other age groups.

Depression is one of the most common mental illness, but current treatments are either ineffective or lead to side effects in up to 50% of youth. In youth, medications are often borrowed from adult population not accounting for age-related brain differences. New solutions are needed to address major gaps in treatment of youth mental health.

Dr. Farzan is collaborating with physicians, neuroscientists, engineers, and health authorities to develop and apply more precise and innovative methodologies to study the brain and address this gap. She is combining non-invasive brain stimulation and brain monitoring technologies to study what may underlie depression in young age, and how each treatment affects the brain. She is also developing non-invasive brain stimulation technologies for youth that do not respond to medications or behavioral therapy. This research has tremendous potentials for leading to introduction of a new therapy for youth who are failing currently available treatments.

Orthogonal multicolour high-affinity tags for RNA imaging and manipulation

RNA plays a very important role in the regulation of gene expression. Yet, the spatial and temporal dynamics of RNA are still poorly understood, mainly due to the scarcity of effective and simple RNA imaging and purification techniques.

The development of technologies that simultaneously allow imaging, purification and manipulation of multiple RNAs in live cells promises to enable the study of RNA in development, metabolism and disease, which is essential for understanding the control of gene expression in diseases such as autism, cancers and type II diabetes.

Dr. Dolgosheina will develop a multicolour RNA-based imaging method that will allow researchers to simultaneously visualize two RNAs in living cells, while concurrently purifying and/or manipulating RNA interactions with other biomolecules. This new technology will build on, and dramatically increase the capabilities of the bright, high affinity RNA Mango system that she developed during her PhD.

The proposed project is working on an outstanding international problem, and since these tools are urgently needed, the research has attracted significant national and international attention.

This research project will 1) result in international level talks and publications, 2) bring together some of the best international researchers in RNA biophysics and 3) result in intellectual property development, industrial research and training and commercialization via a rapidly growing Canadian biotechnology company, Applied Biological Materials (Richmond, BC).

Novel 18F-fluorinated amino acids as oncological PET radiotracers

Positron emission tomography (PET) is a non-invasive imaging technique used to detect tumours and provide information about a patient’s response to treatment. PET generates a 3D image of the inside of a patient’s body and highlights the location of tumors through detection of a radiotracer administered before generating the image. One of the most common forms of radiotracers are small, drug-like molecules containing a radioisotope that bind to or accumulate in cancer cells, precisely locating tumours. 

While many radioisotopes can be used for PET imaging, [18F] is arguably the most desirable due to its high positron output, small atomic size, metabolic stability and worldwide network of production facilities. Despite these advantages, the synthesis of [18F] radiotracers presents many challenges that have limited the scope of radiotracers available for oncological PET imaging. Thus, the majority of oncological PET imaging relies on a single radiotracer: [18F]-FDG, a sugar analogue that preferentially accumulates in cells that have increased metabolism (i.e., cancer cells). 

Unfortunately, [18F]-FDG is not cancer-specific and also tends to bind to other tissues such as brain and bladder, and at sites of inflammation, limiting its utility for detecting tumors in those areas. In recent years there has been considerable interest in identifying complementary radiotracers to FDG, and much attention has focused on the synthesis of 18F-labelled amino acids, which also accumulate in rapidly dividing cancer cells. Dr. Britton’s lab has recently discovered a method for incorporating the [18F] radioisotope into complex drug precursors without the need for elaborate precursor synthesis. 

Dr. Britton aims to:

  • Rapidly expand the number of available amino acid radiotracers using new unique capabilities.
  • Evaluate promising lead radiotracers for oncological PET imaging.
  • Advance selected radiotracers into preclinical animal studies.

In addition to these research aims, Dr. Britton has filed a provisional patent application and will work with the SFU Innovation Office to identify an industrial partner for this new technology. These new amino acid radiotracers could have a profound impact on the early detection of cancer and positively impact the lives of many British Columbians.

Elucidating the effect of O-GlcNAc modification on protein stability

The glycosylation of proteins with O-GlcNAc is a ubiquitous post-translational modification found throughout the metazoans. Deregulation of O-GlcNAcylation is implicated in several human diseases including type II diabetes, Alzheimer’s disease, and cancer.

 

However, the basic biochemical roles of O-GlcNAcylation remain largely unanswered. Several recent studies have demonstrated a clear link between O-GlcNAc and cellular thermotolerance.

 

It is likely that a basic function of the O-GlcNAc modification prevents the unfolding or aggregation of target proteins. Dr. King will investigate its role in protein stability through series of biochemical and biophysical experiments to probe the effect of O-GlcNAc on protein unfolding, folding, and aggregation. The results of this research will provide important insights into the basic molecular mechanisms governing O-GlcNAc deregulation in human disease.

 

End of Award Update: July 2022

 

Most exciting outputs

The modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) is a widespread post-translational modification (PTM) that is dysregulated in several human diseases including type II diabetes, Alzheimer’s disease and cancer. However, research progress in this area is hampered by the fact that it is challenging to detect O-GlcNAc on proteins. Further, the basic biochemical roles of O-GlcNAcylation remain largely unanswered.

 

Therefore, we developed a mass spectrometry based method to precisely map sites of O-GlcNAc on proteins. This method employs a UV laser to produce a diversity of O-GlcNAc retained fragment ions, enabling mapping protein modification sites with unprecedented precision.

 

We then explored the role of O-GlcNAc as a biochemical regulator of protein stability. We developed a new high-throughput approach to profile the effect of O-GlcNAc on the thermostability of the proteome. Using this method, we identify several proteins that are regulated by O-GlcNAc. Interestingly, the majority of these proteins display an O-GlcNAc dependent decrease in stability, challenging the prevailing view of O-GlcNAc as being a predominantly stabilizing modification. Thus, we show that O-GlcNAc is a bi-directional regulator of protein stability. We deliver a powerful approach that provides a blueprint for determining the impact of, in principle, any PTM on the thermostability of thousands of proteins in parallel.

 

Impacts so far
This work delivers powerful tools for exploring the role of O-GlcNAc and other labile PTMs as regulators of protein biochemistry.

 

Potential future influence
Decreased levels of protein O-GlcNAcylation is associated with Alzheimer’s disease. However, the basic biochemical mechanisms underlying this association remain unknown. Here we show that O-GlcNAc regulates the stability of several proteins within human cells, a phenomenon that may impact cellular protein levels in Alzheimer’s disease. This fundamental research is important for understanding the impact O-GlcNAc has on protein structure and stability, particularly in the context of its dysregulation in neurodegenerative disorders.

 

Next steps
We plan to continue exploring the influence O-GlcNAc has on protein structure and function. In doing so, we hope to improve our understanding of the fundamental mechanisms underlying neurodegeneration. This research may ultimately provide knowledge that contributes toward the development of new therapeutic strategies.

 

Useful links

Development of improved substrates for live cell imaging to aid in discovering new glucocerebrosidase therapeutic agents

Parkinson’s disease (PD) is a neurodegenerative disorder that affects millions of people worldwide, with no standard treatment currently available. Therefore, there is a major need for new therapeutic agents to treat or prevent the progression of PD. One promising solution involves targeting the protein glucocerebrosidase (GCase) encoded by the gene GBA1. Studies have shown small molecules that increase GCase activity could help prevent the progression of PD.

Dr. Ashmus will use a combination of organic chemistry, chemical biology, and cell biology to discover new therapeutic agents that increase GCase activity. Fluorescently-quenched substrates will be chemically synthesized and used in enzymatic assays to monitor GCase activity in vitro and in neuroblastoma cells. The assay will then be adapted and optimized for use in a high-throughput screen of compounds from the Canadian Glycomics Network and from a natural products collaborator, Roger Linington, at SFU.

The results of this research could produce new lead compounds that increase GCase activity. In addition, the compound screen could aid in identifying new therapeutic targets for PD, which would drive preclinical translation research in this area.

End of Award Update – March 2022

Most exciting outputs

An exciting and successful specific output as part of the project was that we were able to develop a newly designed probe that performs better than the original probe the Vocadlo Lab published and patented back in 2015. The new probe is also capable of being used in a high-throughput screening in live cells. Moreover, the new design led to the development of probes that could for the first-time target other disease-related enzymes of interest in live cells and led to a high-impact publication in Nature Chemical Biology.

Impacts so far

While the main purpose of the research project failed to discover any lead compounds that could be developed as a potential therapeutic agent for Gaucher/Parkinson’s disease, the steps (develop a better probe and optimize use for screening) required to reach the point of running the screen were successful. The data collected (unpublished) has helped secure funding for the Vocadlo Lab and led to collaborations with biotech companies interested in targeting the same enzyme.

Potential future influence

I think some of the work described briefly will start to gain more attention in the next few years. Over the past year or so, I have noticed an increased interest from research institutes and biotech companies in studying enzymes found within the lysosome. This is in part because more of these lysosomal enzymes are being linked to neurological diseases so having biochemical tools that can study them in live cells will be desired. I think some of the probes we have developed over the past couple of years will be of interest to a broader scientific community.

Next steps

The work searching for potential therapeutic agents for Gaucher/Parkinson’s disease is currently ongoing. The majority of my research efforts have shifted to developing and evaluating novel probes targeting other disease-related enzymes. One notable example is a new project collaborating with an expert clinician in Fabry’s Disease. Using one of our recently developed probes, we aim to advance current diagnostic methods and improve dosing and timing of current therapeutics for Fabry Disease patients. I am excited to see some of my work being used in a clinical setting and hope this can lead to something more fruitful in time. Dissemination of the work will be continued through publications, presentations at conferences and through social media platforms.

Useful links

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.

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.