Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 55 million people worldwide. With no cure or prevention, AD remains a high priority challenge for the Canadian health care system. researchers struggle to develop effective treatments due to poor lab models that do not fully mimic the human brain. This project will create an advanced 3D brain model using patient-derived stem cells to better study early AD stages, focusing on the role of the Amyloid beta protein. By creating a more accurate brain model, this research will help us understand AD more clearly and find new treatment options without the need for animal testing. Findings will be shared widely with stakeholders and patients’ organizations. A group of people with dementia and their caregivers will share their experiences to help guide the research, ensuring it stays patient-focused and promotes mutual learning.
Research Pillar: Biomedical Research
Unraveling Apolipoprotein E’s Role in Alzheimer’s Disease: Insights into miRNA & Glial Regulation and Amyloid Pathology.
• Alzheimer’s disease (AD) is a brain disorder that some people develop as they age. It affects memory and thinking. A protein called ApoE is important in managing fats in the body and supporting brain health. An abnormal variant of APOE4, increases the risk of developing Alzheimer’s, but scientists don’t know why.
• Research shows that mice without ApoE or with human APOE4, and humans with APOE4, have similar problems with fat metabolism, memory, and brain health. Since the retina, the light-sensitive layer at the back of the eye, connects directly to the brain, studying it can provide important clues about how Alzheimer’s affects the brain.
• We will analyze brain, retina, and tear samples from mice without ApoE and those with human APOE4 to look for cell-level changes linked to inflammation, harmful protein buildup, and nerve damage. Tear samples from AD patients with and without APOE4 will also be studied. Results will be shared through workshops, scientific papers, and policy briefs.
• Our goal is to identify early warning signs of AD and understand how ApoE contributes to brain and eye damage. The findings may lead to simple, risk-free tear tests for early AD detection and inspire new treatments targeting ApoE pathways.
Effect of Lateral Meniscus Posterior Root Tears and Repairs on the Mechanics of the Loaded Knee
We will study how a lateral meniscus root tear, a common knee injury, impacts joint mechanics and whether a root repair can restore mechanics to normal. This is important because joint mechanics must be normal to protect the knee from osteoarthritis (OA) later in life. Menisci are crescent-shaped structures that attach to the top of the shin bone at the tips of their crescent shape, called the roots. There is an inner (medial) and outer (lateral) meniscus in each knee. They spread out load to reduce knee stress. Tears to the roots of lateral menisci are a common sport injury. A torn lateral meniscus cannot spread out as much load. This can lead to future knee OA. Lateral root tears can be repaired by stitching the torn root to the bone. This has helped the lateral meniscus spread out load again in cadavers and computer models, but whether it helps in a living person’s knee remains unknown. We will use a special MRI scanner that can image people standing up with their knee loaded. We will measure joint mechanics in patients before and after lateral root repair. This will inform us on how lateral root tears and repairs alter the mechanics of loaded knees, giving insight into mechanisms that can lead to or prevent future knee OA.
Hormones and Inflammation among Women Living with HIV
HIV is a lifelong condition. While effective life-sustaining treatments have increased life expectancy, in Canada, women living with HIV (WLWH) live 7 years less and experience age-related illnesses earlier than men living with HIV and live 5-10 years less than women without HIV. The British Columbia CARMA-CHIWOS Collaboration (BCC3) is a study of WLWH and control women without HIV. It takes a holistic society-to-cell approach to address questions on healthy aging and involves WLWH in the research. Sex hormones are more often low in WLWH, perhaps due to HIV or its treatment. Low hormone levels impair immune function and increase inflammation, yet the link between HIV, hormones, and inflammation remains largely unexplored. My project will assess how levels of three key hormones – estradiol, estrone, and testosterone – known to be associated with age-related illnesses in women, are linked to immune responses and markers of inflammation. Ongoing knowledge sharing will include in-person and virtual events throughout BC with presentations, art-based activities, and take-home materials. This project will help understand the biological impacts of altered hormones in WLWH, and inform potential avenues to improve care for women.
Personalized nutrition for inflammatory bowel disease: Predicting dietary responses based on gut microbiome and baseline factors
Every patient with inflammatory bowel disease (IBD) wonders what to eat to improve their symptoms. Many believe that diet affects disease progression and no one-size-fits-all diet exists for everyone. Our controlled trial in adults with IBD supported this idea when the symptoms of almost 50% of adults with IBD in either standard dietary therapy or the Mediterranean-style diet group were ameliorated, though to varying extents. This variability arises because each patient’s biology and lifestyle are unique. People’s gut microbiota, trillions of microbes living in intestine, is highly personalized and can mediate their physiological responses to diet. However, remaining concern is that chronic inflammation in IBD disrupts the gut microbiome, allowing harmful bacteria to thrive and beneficial ones to vanish. Diet alone or conventional probiotic treatments can’t fix this imbalance. I will investigate how patients’ specific characteristics and gut microbes influence their response to certain diets and how these synergize with a newly engineered probiotic designed to thrive in an inflamed gut. These findings will be used for a future clinical trial using our derived algorithm to prescribe personalized diets and a bioengineered probiotic.
Matriptase-Selective Radiotheranostics for Metastatic Carcinoma
Metastatic cancer, in which cancer cells invade healthy distant tissue, is the leading cause of death in Canada. Epithelial breast, colon, and prostate cancer of the outermost tissue lining are the most prevalent forms of metastatic cancer and require better tools to prevent life-threatening outcomes. Treatments such as surgery and chemotherapy are either impractical for metastases, invasive, or toxic. The goal of this work is to develop a radioactive molecule that targets matriptase, an enzyme which supports tumor growth and metastasis. A set of molecules will be made, labelled with a radioactive tag, and screened for binding. Conveniently, the radioactive source is interchangeable for imaging or targeted radiotherapy. Using a specialized camera, tumor radioactivity can be noninvasively tracked to classify disease progression. Using a different radioactive tag, radiation can also be delivered to exclusively kill matriptase-positive tumor cells. The lead candidate is expected to enable tumor staging and improve patient outcomes by impeding tumor growth and spread. It may also be used to monitor response to therapy and guide clinical decisions, representing a major advance in the management of metastatic epithelial cancer.
How do neurons in breast cancer tumours control anti-tumour immune responses?
Immune cells can be very effective at killing cancer cells, but tumours have the ability to suppress the immune system. This is why some of the best cancer therapies work by turning the immune system back on. To do this, it is key to understand what controls immune responses in the tumour. In inflammation, it has been shown that neurons can control the immune system. Interestingly, there is evidence that by removing neurons, cancer growth is reduced. We have discovered that when the “heat sensing” TRPV1 neurons are removed in mice, the tumor will grow much slower. We will looked at changes in immune cells using flow cytometry, which allows us to measure over 20 different immune cell types and discovered that these mice may have lower numbers of a rare cell type called ILC2. Next we are trying to understand how neurons are affecting these cells and the tumor growth. Finally, we will design a cell culture system where neurons and mini-cancers will be grown together to see if the tumors are secreting something that changes the expression of genes by neurons. This will lead to the development of novel therapies that activate the immune system by targeting neurons and provide new information on therapeutic avenues for breast cancer.
Impact of TSC2-deficient neural cells on microglial structure and function in an induced human pluripotent stem cell model of tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a rare genetic disease caused by mutations in the TSC2 gene. The TSC brain develops malformed tissue clusters called cortical tubers (CTs), which cause epilepsy and cognitive problems. CTs result from abnormal cell differentiation, where clusters of enlarged neural stem cells, astroglia, and hyperactive neurons form. CTs notably present markers of cell stress and inflammation, which are known to affect organelles, cell differentiation, and neuron function in CTs. CTs are surrounded by microglia, the resident immune cell of the brain, required for proper brain function and the main drivers of inflammation. Though known to be a feature of TSC brain lesions, the role of microglia in CT formation is completely unknown. Therefore, I will investigate if microglia contribute to CT formation and, study for the first time, how the interaction with TSC2 mutant cells affect microglial function. Using advanced molecular and imaging techniques, I will study if microglia affect CT formation in a co-culture model of human pluripotent stem cell-derived microglia and TSC2 mutant neural cells. Our results will finally elucidate the role of microglia in CTs, a critical advance to uncover novel treatments for TSC.
Advancing Cardiovascular Research: Developing Vascularized Heart Organoids-on-Chips Integrating Immume Cells
Organoids, miniature organ models grown from stem cells, replicate the complexity of actual organs on a scale of about one millimeter. They exhibit similar morphology and functions but lack crucial elements like vasculature and immune response. In contrast, organs-on-chips, while providing dynamic microenvironments, typically use less sophisticated biological models. By combining these technologies, we can leverage the biological accuracy of organoids with the dynamic capabilities of organs-on-chips. This synergy aims to replicate in vivo physiology, enabling a more accurate study of disease characteristics and drug responses.
The project’s centerpiece is to engineer heart organoids-on-chips, with functional vascular and immune components, to investigate hypertrophic cardiomyopathy (HCM). We will evaluate the efficacy of drugs in mitigating hypertrophic responses. In addition, the study will include perfusion of immune cells to analyze the role of inflammation in HCM progression, investigating immune cell recruitment.
This initiative coincides with the U.S. FDA’s pivot from mandatory animal testing for new drugs, marking a significant shift towards more relevant human-based models in drug development.
Cerebrovascular physiology of circulatory death in patients undergoing medical assistance in dying (MAiD)
Patients undergoing medical assistance in dying (MAiD) can qualify as organ donors. Donation commences after death, which is declared when blood pressure drops below a certain threshold. We believe that a low enough blood pressure means the brain is no longer receiving blood, which represents true death, after which donation can begin. The time it takes for blood pressure to become low enough (ischemic time) can cause damage to organs because of reduced blood flow. If it takes too long for blood pressure to reach the threshold, too much damage occurs, and organs are discarded. The threshold value of blood pressure is based on studies of critically ill patients in the intensive care unit. We are not sure if the same thresholds would apply to patients undergoing MAiD, as their underlying physiology is different. We think the threshold would be higher for patients undergoing MAiD. We will measure blood flow velocity to the brain in patients undergoing MAiD using transcranial doppler. If blood flow stops at higher blood pressure levels than currently used cutoffs, this would reduce ischemic time and reduce damage to potential donated organs. We will report our results in scientific journals and through organ donation organizations.