British Columbia (BC) and Canada have some of the world's highest rates of multiple sclerosis (MS). The goal of this research is to find out how safe and effective the drugs used to treat MS are when used in the everyday, real world in BC and Canada.
To achieve these study goals, I have two main study Themes. The first Theme focuses on how effective the MS drugs are. I will examine whether the MS drugs can extend life expectancy or prolong a person's ability to stay mobile and walk. I will also look at whether the MS drugs have a beneficial effect on reducing the number of times a person with MS is admitted to a hospital or visits a physician. The second Theme focuses on side effects, including whether the MS drugs are associated with harmful effects, such as cancer, stroke or depression. I will be able to compare the different MS drugs to each other. Also, I will see if men and women or people of different ages and with other illnesses (such as having both MS and diabetes) respond to the MS drugs differently.
My research findings will help people with MS and their physicians when trying to make decisions as to which MS drug might be best for them. Ultimately, this study will benefit the >90,000 people living with MS in Canada.
Mild traumatic brain injury (mTBI), commonly known as concussion, is a major public health concern. Around 42 million of the world's population sustain mTBIs annually. In Canada, ice hockey has the highest sports concussion rates in children and youth. In British Columbia, 2.4 million dollars were spent on hospitalization for mTBI in 2010. Furthermore, recent studies have linked multiple mTBIs from sports with heightened risk of long term brain changes. Despite the prevalence, the diagnosis and prevention of this condition is currently ineffective, due to the lack of knowledge of the injury mechanism.
In the proposed research program, I aim to gain a better understanding of the mechanism of mTBI. Specifically, I will study sports-related mTBI in ice hockey athletes, and investigate the effect of head accelerations on brain function. Players will be instrumented with mouthguard sensors to measure head motion and wearable electroencephalogram (EEG) sensors to measure brain response during practices and games. From the analysis of these data, we will gain a better understanding of the cause of injury. This understanding can help develop better diagnostic and prevention technologies to improve concussion management in and beyond BC.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths mostly due to the absence of symptoms as the cancer develops. This leads to diagnosis after the tumor has already become widely invasive and cannot be surgically removed. Unfortunately, surgical removal of early stage tumors is the most effective treatment option and other treatments, such as chemotherapy, are woefully ineffective.
Thus, there are two major fronts where research could improve the outcomes of pancreatic cancer patients:
- early detection and
- more effective treatments. Early detection requires knowledge of the events associated with tumor development, while improving treatments requires a thorough understanding of pancreatic cancer. It is clear that a 'one-size-fits-all' strategy has largely been ineffective for pancreatic cancer. We hypothesize that this is partly because PDAC is a 'catch-all' diagnosis for tumors that look the same, but may have different properties due to differences during their development. Our research program seeks to identify these differences and ultimately leverage the differences to improve patient outcomes through the development of personalized treatments.
Michael Smith Foundation for Health Research/The Pacific Alzheimer Research Foundation Post-Doctoral Fellowship Award
Millions people worldwide are currently afflicted with Alzheimer’s disease (AD). In the absence of a complete understanding of the disease, therapeutic trials have been unsuccessful and there still remains no cure. Biomarkers that can reliably detect AD at the earliest possible stage are essential for disease monitoring and drug therapy. The development of a biomarker for AD that can be translated to a rodent model of AD would also be useful in drug discovery. A validated biomarker could profoundly change the rate of the development and implementation of treatments for AD by enabling rapid high throughput screening of new drugs. Furthermore, the development of a robust method for biomarker detection which can be translated to a clinical laboratory setting would be an invaluable tool for AD diagnosis and monitoring. AD patients have deposits of proteinaceous plaques within their brains.
Our previous research has shown that a protein called melanotransferrin (MTf; also known as p97 or CD228) exists at high levels in humans with AD and is specifically expressed by immune cells associated with plaques in the brain. In contrast, healthy patients show a limited distribution of MTf. Of particular interest, the blood concentration of p97 is also elevated in AD patients compared to age-matched healthy human controls. These preliminary studies are promising but suffer from limited population size and the inherent uncertainty of current AD diagnostic methods (i.e. can only be truly diagnosed post mortem).
We plan to further validate MTf as an AD biomarker in mouse models of AD. This will be accomplished using a revolutionary diagnostic technology known as the SISCAPA assay. This platform offers reliable, robust absolute quantitation of proteins in complex biological fluids, and is already in use across the USA for the diagnosis of thyroid cancer. Using this clinically amenable method, we will monitor AD model mice, and wild type controls, throughout their life and correlate MTf concentration with the degree of neurodegeneration. It is expected that at a young age AD mice will be indistinguishable from healthy controls but as plaques appear in the brain, so too will MTf levels rise. These results will illuminate the timeline and intensity of MTf elevation as it relates to neuropathology. We will also establish the baseline for MTf in healthy or pre-AD subjects. These discoveries have the potential to change the course of detection and treatment of AD.
Michael Smith Foundation for Health Research/The Pacific Alzheimer Research Foundation Post-Doctoral Fellowship Award
Type 2 diabetes (T2D) patients have an increased risk of developing Alzheimer’s disease (AD). However, the underlying mechanism is poorly understood. Human islet amyloid polypeptide (hIAPP) aggregates, occurring in ~95% of T2D patients, induce a variety of pathological processes that are contributing factors to AD neuropathology. In current proposal, we attempt to investigate the effect of hIAPP aggregation on the Alzheimer’s development in T2D and the potential mechanism by conducting cell and animal experiments. Additionally, novel transgenic mouse models of diabetic AD will be generated to mimic the natural process of AD development in diabetics.
This study will help us to define the prevention and treatment of diabetic AD. Dissemination of the findings from this study will be done in different ways to make sure that the largest number of people will hear, understand and benefit from this novel research project. The experimental results will be published as research articles on academic journals and presented at scientific conferences, such as Society for Neuroscience annual meeting and Canadian Diabetes Association professional conference. Educational events and learning series will be held in the community, such as Cafe Science and public lecture series where we can engage the public with our research study, answer their questions directly and stimulate discussions.
End of Award Update
Source: CLEAR Foundation
Dr. Zhang’s research focused on creating a better understanding of why type 2 diabetes patients have an increased risk of developing Alzheimer disease. This research identified the important role of human islet amyloid polypeptide (hIAPP) in diabetes-induced dementia. Targeting hIAPP may be a valid approach for preventing and treating dementia in diabetes mellitus.
A dental implant is a screw-like device that is surgically placed in the jawbone to provide a foundation for artificial teeth. This involves precise removal of bone using drills, which is often risky because of proximity to delicate structures such as the maxillary sinus, orofacial nerves, and blood vessels. Mistakes in the drilling path may result in permanent nerve damage, life threatening hemorrhage, or injuries to adjacent teeth. This research project aims to reduce errors in the process by developing an objective and sensor-based method to assist practitioners in conducting the drilling process.
Our method will analyze the sounds generated during implant drillings to monitor the process and recognize different bone tissues, providing real-time feedback on whether the practitioner is taking the correct line. Proof of concept exists in that drilling sounds have already been used in similar applications to discriminate between tooth materials.
To collect the data, we will drill sample jawbones (pig or cow) as we would in typical implant surgeries. We will record the sounds produced by drilling bone tissues under different conditions such as direction, feed rate, speed, and applied forces. Advanced signal processing methods such as machine learning will analyze the data to allow us to discriminate between different bone tissues.
We will optimize the resulting algorithm to produce an aid for practitioners that will improve the safety and precision of their dental implant surgeries. Future work could include further customizing the algorithm to extend its use to other medical procedures that involve bone drilling such as orthopedics, spine, and ear surgeries.
Michael Smith Foundation for Health Research/Vancouver Coastal Health Research Institute Post-Doctoral Fellowship Award
Stroke is a debilitating disease and the third leading cause of death in Canada. It stems from disrupted blood flow to the brain, leading to cell death due to lack of oxygen and glucose. A major consequence of stroke is edema (swelling of brain cells and tissue), and is the principal cause of death in stroke patients. Current treatments for brain edema, such as osmotherapy and surgical decompression, are relatively crude and ineffective.
We have identified a new possible cause of stroke-induced edema in SLC26A11, an ion transporter that is expressed in neurons throughout the brain. Our previous work shows that it allows chloride ions to enter brain cells, bringing excess water into the cells by osmosis. This project will probe our theory that SLC26A11 is a critical trigger of cell death during stroke.
This work could lead to a better understanding of edema during stroke, which could ultimately aid in developing new drugs to treat it.
Atherosclerosis, caused by cholesterol buildup and inflammation in arterial blockages (plaques), is the leading cause of death in Canadians. Cholesterol-loaded cells (foam cells) that collect in plaques make it unstable, leading to heart attacks and strokes. White blood cells called macrophages have previously been thought to be the main cell type accumulating cholesterol in plaques. However, our studies found that at least half of foam cells in human plaques come from artery smooth muscle cells.
Mouse models are routinely used to study and test new therapies for atherosclerosis, but little is known about the contribution of smooth muscle cells to foam cell formation in mouse plaques. Our finding calls into question whether these models are truly applicable to understand the human disease.
We will compare the contribution of smooth muscle cells to foam cell formation in two commonly used mouse models of atherosclerosis to that in human plaque. This will provide valuable information about the utility of those models for understanding atherosclerosis in humans.
Furthermore, we will examine the differences between macrophage-derived and smooth muscle cell-derived foam cells that are related to disease progression, regression, and treatment efficiency.
This research may change how we understand, prevent, and treat atherosclerosis.
Michael Smith Foundation for Health Research/AllerGen Post-Doctoral Fellowship Award
A major focus for mucosal immunology research has been on the types of bacteria that reside in the mammalian intestinal tract. These bacteria are collectively referred to as the microbiota. Disrupting the microbiota composition by antibiotic use has been linked to the development of allergic disease in both human populations and mouse models.
Mice treated with antibiotics early in life acquire an altered microbiota and signs of asthma in a mouse model of allergy. We seek to identify key bacterial species within the microbiota that affect allergy in this mouse model.
Additionally, we plan to explore whether antibiotic treatment affects cells of the immune system. A high level of one particular kind of antibodies (IgE) is associated with allergic asthma development in humans, and treating mice with antibiotics results in high levels of IgE. We will test whether changing IgE levels in mice changes their sensitization to allergens.
If antibiotic use is linked to allergy development, understanding how could allow researchers to develop strategies to soften this effect.
Michael Smith Foundation for Health Research/Rick Hansen Institute (RHI)/International Collaboration on Repair Discoveries (ICORD) Post-Doctoral Fellowship Award
People with spinal cord injury (SCI) are at an increased risk of developing type 2 diabetes. Currently, no studies have investigated type 2 diabetes in people with SCI. We believe it may contribute to the high rate of heart disease among people with SCI.
The aim of the present study is to develop an animal model of SCI combined with type 2 diabetes. We will then use this model to see whether type 2 diabetes progresses more quickly after SCI, whether developing type 2 diabetes after SCI impairs function of the heart, and possible causes of the negative impact of type 2 diabetes on heart function.
Should we find that type 2 diabetes impairs heart function, this will lead to further studies aimed at preventing and treating type 2 diabetes in people with SCI. Our findings could aid in the clinical management and treatment of people with SCI and significantly improve their health and quality of life.
