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.
In healthy humans, blood flow to the brain is regulated such that appropriate amounts of oxygen and glucose are delivered to brain tissue. Even when blood pressure changes or when a region of the brain becomes more active, brain blood vessels react in order to provide sufficient blood to their respective area of tissue. When these processes fail, disease states develop. For example, too little blood flow to the brain for even a few seconds causes fainting and too much blood flow can cause a stroke.
Our understanding of these processes is currently lacking, particularly with respect to the relationships between the sympathetic nervous system (associated with the "fight-or-flight" response), brain metabolism, and regulation of brain blood flow.
This project aims to develop a better understanding of the relationships between these processes.
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/BC Cancer Foundation Post-Doctoral Fellowship Award
High-grade serous ovarian cancers (HGS) have a low five year survival rates at less than 40 percent. This is partly because of high relapse rates due to resistance to platinum-based therapies, which is the current standard of treatment. Although these therapies are effective at treating the primary tumour, cancers develop resistance to platinum drugs in almost all instances and the tumours recur.
How genomic instabilities evolve in HGS tumours and lead to platinum-resistance is poorly understood, and there are currently no biomarkers that give a reliable prognosis. We seek to identify effective genomic biomarkers for determining which HGS patients will respond more effectively to platinum-based chemotherapy.
This project will build on our research group's recent observations of differences in global genomic patterns between platinum-sensitive and platinum-resistant groups. We will analyze an HGS cohort of seventy cases composed of short- and long-term survivors with five year clinical follow-up data by:
- Comparing and contrasting the entire DNA sequence of tumours to the patient's normal DNA to identify global patterns of genomic instability
- Comparing and contrasting genomic profiles from the whole genome of the short-term and long-term survivors
- Studying diversity via deep-sequencing data of the tumours.
Ultimately, the results of this project and future work could allow for a long-term prognosis and optimized treatments for patients with HGS ovarian cancer.
Diarrheal illnesses remain a major cause of sickness and death worldwide, killing approximately 760,000 children under the age of five each year. This project seeks to better understand one major cause: bacteria known as attaching and effacing (A/E) pathogens. This group includes several classes of pathogens: i) a class that causes death primarily among children in developing countries, and ii) a class with potentially life-threatening complications such as kidney failure in both developing and developed countries.
First, the normal community of microbes inhabiting the healthy mammalian digestive tract (the gut microbiota) represents a major challenge for A/E pathogens by competing for nutrients and possibly by producing molecules that inhibit the A/E pathogens. We will investigate how A/E pathogens sense and adapt to the presence of the gut microbiota with a view to gaining insights into their overall infection strategy.
Second, we will seek out species within the gut microbiota that inhibit A/E pathogens. Chemicals that they produce could form the basis of drug discovery programs for novel antibiotics.
Our final objective is to characterize one genetic system that A/E pathogens use to sense their surroundings: the Cpx envelope stress response. This system triggers production of damage-repair proteins when it senses damage to the envelope of the bacterial cell. We will study whether and how these repair proteins are required for A/E pathogens to infect mice. If so, they represent a potential target for developing novel antibiotics.
This project will yield a better understanding of a major cause of illness and death and might give rise to new avenues of research for novel antibiotics to counter it.
Human cells experience DNA damage every day, but DNA repair systems ensure that resulting mutation rates are extremely low. Two main pathways repair severe DNA damage in cells. The 'copying' pathway connects broken DNA ends by copying the missing sequence from the second DNA copy that is present before cells divide. The 're-joining' pathway simply re-joins the broken DNA ends irrespective of the missing sequence. Mutations in these pathways are frequently found in cancer cells, which can accumulate thousands of mutations.
Recent studies show that tumours with mutations that inactivate the copying pathway can be effectively treated with drugs that inhibit the re-joining pathway. After drug treatment, both repair pathways are impaired in tumour cells, whereas normal cells still retain one functional pathway. As a result, doses can be adjusted so that side effects of chemotherapy are milder.
A protein named CDK12 appears to be a regulator of the copying pathway, and cells with abnormal CDK12 are sensitive to drugs that inhibit the re-joining pathway. Mutations in CDK12 have been found in many tumour types. Our preliminary results show that CDK12 regulates an essential cellular process termed 'alternative splicing,' where gene segments are assembled in different orders to create different versions of the same gene.
We will examine how CDK12 changes the alternative splicing of genes after DNA damage, and how this regulation is impaired by mutations in CDK12 that have been found in tumours. Ultimately, this work could lead to new research tools and help to define the population of cancers that can be treated with CDK12-based therapy.
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.
