Research Location: University of British Columbia

Studying motion processing with eye movements in healthy older adults and patients with ophthalmic diseases

As our population ages, an increasing number of Canadians experience difficulties with their vision. Although it is well known that both normal aging and age-related eye disease can affect a person's ability to see fine detail (such as in reading), tests of visual acuity used in regular eye examinations do not provide a complete picture of a person's ability to see in everyday situations, such as exercising and driving, where moving objects are often involved. Moreover, these tests often demand verbal instructions and do not accommodate sufficiently for the multilingual population of Canada with a range of cognitive functions. We propose to develop a technology utilizing eye movements to assess visual motion processing.

Our research will gather scientific evidence to understand the relationship between motion processing and eye movements in healthy seniors and patients with ophthalmic diseases, and whether it is practical to introduce the technology into clinical practice. This quick and non-verbal method of assessing vision provides a potentially cost-effective vision assessment strategy that addresses an important population health issue.

When poor construction leads to destruction: How do structural defects in the light-sensing cells of the eye cause blindness?

Retinal degenerative disorders are inherited diseases that affect tens of thousands of Canadians. The effects are devastating; severe vision loss or complete blindness occurs early in life, resulting in the loss of livelihood, mobility, and independence. There is no cure, and present treatments focus on easing the symptoms of blindness instead of preventing vision loss in the first place.

My research is focused on the prevention of vision loss by understanding how specialized structures in the light-sensing cells in the eye, called photoreceptor outer segments (OS), are made, and how defects in OS assembly result in photoreceptor death and blindness. Using genetically-modified frogs, I have replicated human disease caused by mutations in two genes, prominin-1 (prom1) and photoreceptor cadherin (prCAD). I have determined that these genes are necessary for OS organization, and am now working towards identifying their specific functions.

Identifying the roles of prom1 and prCAD will benefit scientists and patients.  It will further our understanding of how OS are built, a topic of great interest to visual scientists, and aid in the identification of novel therapies for some of the most common human retinal degenerative disorders.

Microbial control of gut environment in IBD

Gut health is closely connected to our microbiota, a unique, constantly evolving, group of trillions of bacteria that live in our bodies. Gut microbes produce compounds that are absorbed into our blood, providing nourishment and also affecting the gut environment. The digestive tract is composed of many different local areas, called habitats, in which physical and chemical properties such as water availability, salt concentration, acidity or temperature are tightly controlled by human-microbe interactions. These habitats are dramatically changed by inflammatory bowel disease (IBD) and in return affect which microbes can survive within them. Despite the importance of the gut environment to IBD, we know little about its effects on the gut microbiota and on the progress of the disease.

I will use a combination of cutting-edge experimental and computational techniques to study the connection between the gut microbiota, the gut microenvironment, and IBD. My laboratory will study tissues from IBD patients to identify what aspects of the gut environment and microbiota can predict flares and remission. We will also study isolated bacteria and study how they respond to, as well as modify, their environment in a mouse model of IBD. This research will lead to health and economic benefits for Canadians, by developing microbiota based therapies for diseases of the digestive tract that affect millions of Canadians.

Developing new anti-cancer drugs that target abnormal signaling networks in cancer

A defining characteristic of cancer cells is their ability to grow and replicate in an uncontrolled manner. Cancer cells have altered signaling pathways that allow them to bypass checkpoints that would normally prevent their rapid growth. STAT3 protein is a master regulator of cancer cell signaling and is found to be overactive in 70 % of cancers. While healthy cells can survive without STAT3, cancer cells become addicted to overactive STAT3 and are sensitive to disruptions in this pathway.

As a result, several drug-like molecules have been explored for their ability to inhibit STAT3 signaling in cancer cells. While some have shown promising anti-cancer effects, issues with selectivity and toxicity have prevented their clinical use. With the goal of identifying better STAT3 inhibitors, my research program uses cutting-edge techniques to determine how STAT3 inhibitors function in cells. We investigate what exactly the inhibitor binds to inside a cancer cell and how that affects STAT3 signaling. We also use these techniques to develop our own STAT3 inhibitors which we then explore as novel anti-cancer agents. Our ultimate goal is to produce new medicines that can help patients win their battle against cancer.

Identity in mental health: A focus for early intervention and improving social functioning

Personal identity–one's psychological sense of personal continuity–is an important aspect of mental health, informing one's motivations, behaviours, and social relations. Disruptions in identity can contribute to prevalent conditions such as personality disorders. Indeed, distorted identity is a core aspect of personality dysfunction and disorder, contributing to considerable negative health and social outcomes–and a prominent challenge for health care providers and systems. Interventions that strengthen identity during young adulthood may be a potent way to mitigate personality dysfunction, preventing entrenched impairment and setting a course for positive mental health.

This proposal features a novel psychosocial intervention aimed at strengthening identity and reducing personality-related dysfunction among vulnerable young adults–tested in a randomized controlled trial. The intervention is designed for use by non-specialists to maximize transferability and impact on access and quality of care. Building on the applicant's work in maladaptive personality and identity, the project is set within a broader program of research on identity-focused intervention, including within early psychosis and recovery from alcohol misuse.

Advancing nutritional hematology to reduce the burden of anemia and inform nutrition policy

Anemia is a condition in which there is a decrease or destruction of red blood cells causing inadequate transport of oxygen throughout the body. It is a major public health problem affecting ~25% of the global population, or ~9 million Canadians of all ages.

In infants and children, anemia can impair brain development and decrease learning ability. In adults, it can cause fatigue, lower work capacity and increase the risk of adverse pregnancy outcomes (e.g. low birthweight). Causes of anemia can include micronutrient deficiencies (e.g. iron or folic acid), infection and disease, and genetic hemoglobin disorders (e.g. thalassemia). Understanding the causes of anemia is critical to inform appropriate strategies to prevent and treat anemia, and to reduce the risk and burden of disease.

Dr. Karakochuk's research program will seek to improve diagnostic methods and investigate novel biomarkers for anemia and iron deficiency, and assess the risk-benefit of iron and folic acid supplementation programs designed to treat anemia and other chronic diseases. The ultimate goals are to reduce the burden of anemia and to inform safe and effective nutrition policy, programs and interventions for individuals and populations in Canada and globally.

Promoting Mental Health and Addressing Substance Use in Canadian Youth through Collaborative Research and Intervention

Mental health and substance use (MHSU) challenges are leading health issues facing youth globally. In Canada, 20% of the youth population experiences mental health disorders, and youth aged 15-24 have the highest rates of past year substance use and related harms. To address these concerns, MHSU researchers and advocates argue for a population health approach incorporating promotion, prevention, and treatment within a 'healthy public policy' framework. Yet while much research has focused on the prevention and treatment of youths' MHSU challenges, there has been limited focus on mental health promotion.

Further, while there is growing recognition of the importance of engaging youth in matters that affect their lives, there is a paucity of evidence-based guidance on how to do this effectively. This study contributes to addressing these substantial gaps by exploring how to meaningfully engage youth in the policymaking process to promote MHSU outcomes. Participatory approaches and mixed methods are being used to generate knowledge and inform a framework to guide youth-engaged research and action to better tackle the MHSU needs of Canadian youth.

Rethink Endometriosis: Genomics and Microenvironment Influence on Biology and Malignant Potential

One million Canadian women are affected by endometriosis annually. There is little investment in research, and socioeconomic cost, >$4 billion annually in Canada, continue to climb owing to lost productivity, sick days, treatments for frequent pain, infertility and depression. Most critically, affected women may have up to a 10-fold increased risk of developing specific types of ovarian cancer. There are no biological features that predict if endometriosis will result in severe or chronic pain, infertility, or cancer.

In 2017, my work identified cancer mutations in the DNA of endometriosis, a feature seen only in cancer.

Since then, I have established a research program with two goals:

  1. to examine association between specific mutations and types of endometriosis.
  2. to understand how other biological features, such as the immune-system, may be affected by mutations and contribute to the establishment of endometriosis, and progression to cancer. Cancer mutations are present in all types of endometriosis, including those with no risk of cancer. Additional work is needed to understand how these mutations influence the biology and symptoms of both endometriosis and their associated cancers, as well as establish management strategies.

Targeting amyloid propagation in Alzheimer disease: Structures, immunology and extracellular vesicle topology

Dr. Neil Cashman is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

As the incidence of Alzheimer’s disease (AD) continues to increase worldwide, a treatment or prevention for AD is a top priority for medical science. One of the main hallmarks of the disease are protein plaques that form inside the brain, and are believed to be the primary cause of brain cell (neuron) death. Research has shown that the protein, amyloid-β (A-beta) is the main component of these plaques.

 

While there are many forms of A-beta produced by brain cells, the specific one that causes AD is hotly debated by scientists. Dr. Neil Cashman, a neuroscientist and neurologist at the University of British Columbia (UBC) has discovered a novel way of identifying a unique form of A-beta that can become toxic and inflict the damage associated with AD.

 

Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, and his team have discovered immunological compounds that specifically recognize the potentially toxic form of the A-beta protein, and can exclusively detect this form in the brains and spinal fluids of AD patients. Furthermore, Cashman found that normal, healthy control patients did not have this dangerous form of A-beta. It was also found that some healthy people naturally develop immune responses against their A-beta oligomer-specific target.

 

Cashman’s team will exploit this knowledge and their unique tools to learn how toxic A-beta proteins can spread from cell-to-cell and region-to-region in the brain causing AD. The discoveries by Cashman’s lab may provide an effective early diagnostic tool for the disease, and ultimately could lead to the development of a preventative vaccine to neutralize the toxicity of abnormal A-beta, potentially slowing or stopping the spread of neurodegeneration in the brain.

 

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

We know that Abeta oligomers, a “seeding species” in Alzheimer’s disease, are predominantly spread in the brain via naked protein aggregates, and not through extracellular vesicles.

 

Why is this knowledge important?

The development of oligomer-specific antibodies (Acumen, ProMIS Neurosciences) has enabled selective immunotherapies for Alzheimer’s disease that target the toxic molecular species of AD, while sparing precursor protein (APP), Abeta monomers, and Abeta fibrils in the form of plaques. Binding to any of these non-oligomer molelcular species of Abeta lead to adverse effects, most prominently plaque-disruption linked ARIA – a form of neurovascular brain edema.

 

What are the next steps?

Dr. Cashman is now the full-time Chief Scientific Officer of ProMIS Neurosciences, which is conducting IND-enabling studies of the oligomer-specfic antibody PMN310. Human phase 1 trials are set for late 2022 or Q1 2023.

 

Publications

Propagated protein misfolding of SOD1 in ALS: Exemplar for neurodegeneration

MSFHR supported Dr. Neil Cashman’s award as one of two interprovincial teams from across Canada funded through Brain Canada’s Multi-Investigator Research Initiative (MIRI) in 2013. The MIRI supports the research of multidisciplinary teams and aims to accelerate novel and transformative research that will fundamentally change the understanding of nervous system function and dysfunction and its impact on health. MSFHR committed funding over three years to support the work of Cashman’s BC-based research activities and research led by fellow MIRI recipient Dr. Terrance Snutch on the role of brain calcium channels in brain disorders. Additional support was provided by Genome BC, the University of British Columbia (UBC)/Vancouver Coastal Health and two Quebec-based research institutes.

Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, is a progressive fatal disease that affects the nerve cells responsible for muscle movement (motor neurons). ALS is characterized by the systematic paralysis of muscles due to the progressive death of motor neurons. An estimated 2,500 to 3,000 Canadians suffer from the disease, for which there is no cure or effective treatment. Each day, two to three people are lost to ALS, with 80 percent of affected individuals dying within two to five years of diagnosis. 

A study led by clinical neurologist and neuroscientist Dr. Neil Cashman at UBC has revealed how factors that cause ALS can be transmitted from cell to cell throughout the nervous system and suggests the spread of the disease could be blocked, pointing to new therapeutic approaches.

Neurodegenerative diseases like ALS belong to a larger group of illnesses known as protein misfolding diseases. Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, built on his hypothesis that certain proteins implicated in ALS, when abnormally shaped or misfolded, are prone to accumulate and cause motor neuron death. This disease mechanism has also been found in other neurological diseases, such as Alzheimer’s and Parkinson diseases. 

Cashman’s team used therapeutic antibodies that target and block these misfolded proteins to better understand the protein misfolding process and how the disease is transmitted throughout the nervous system. Cashman’s work can lead to identifying the best ways to stop the progressive neurological damage seen in ALS through the development of targeted treatments.