Interstitial lung disease (ILD) is a diverse group of illnesses with a variety of causes. The current approach to diagnosing ILD depends on the specific patterns observed on imaging studies (CT scan) and lung biopsy. There is increasing evidence that an individual’s genetics play a complex and important role in determining disease behaviour across different ILD subtypes. This study will examine whether common genetic risk factors predispose patients to different forms of ILD, influence treatment response, and predict prognosis. Investigating these genetic risk factors will improve our understanding of the biology that drives ILD and will help to develop a better system for ILD classification and diagnosis.
Year: 2022
Fibrinogen promotes a microglial-mediated inflammatory response following adolescent repetitive mild traumatic brain injury
Concussions are a major health issue in Canada. Adolescents are an at-risk population for concussions because they are in an age range that is often engaged in contact sports and high-risk activities. Microglia, the brain’s resident immune cells, respond to these injuries, causing an inflammatory response. Concussions can damage brain blood vessels, promoting the release of fibrinogen, a protein not present in the healthy brain. Fibrinogen interacts with microglia, promoting an inflammatory profile that can alter neuronal functioning, leading to behavioural deficits. This project will block fibrinogen’s interaction with microglia using an ecologically valid rodent model of concussion. We will assess short- and long-term memory with well-known behavioural tests. In addition, we will assess microglial activation and type using immunohistochemistry, and assessing neuronal connectivity using field electrophysiology. Adolescence is a period of significant development marked by rapid learning and substantial brain growth/maturation. As such, expanding and fully characterizing changes in brain circuitry mediated by fibrinogen/microglia interactions following concussion may provide avenues for preventative and therapeutic interventions.
Cryo-EM studies of activators and inhibitors of KCNQ1 and KCNQ1:KCNE1 channel complexes
Type 1 Long QT syndrome (LQT1) and Short QT syndrome (SQT) result in life-threatening irregular heartbeats that can cause sudden death. LQT1 affects around 1 in 2,500 adults, whereas SQT may impact twice as many individuals, with high prevalence of congenital LQT in a First Nations community in Northern BC. Current treatments are inefficient and therefore, new therapeutic strategies are needed. Abnormalities of the protein, KCNQ1, result in these diseases. Normal KCNQ1 function moves charged ions through heart membranes. We generally know how KCNQ1 functions in health and disease; however, the exact mechanisms are not yet fully understood. We need to study the 3D structural changes that happen to KCNQ1 in the presence of certain compounds to understand how KCNQ1 functions. I will study the 3D structures of such complexes by using cryo-electron microscopy, a technique to study structural biology, and functional characterization. The new knowledge that will be produced will help better understand how such proteins cause disease and lead to new therapeutics for better human health.
Cholesteryl ester transfer protein-mediated regulation of HDL cholesterol levels and clinical outcomes in sepsis
Sepsis is the overwhelming immune system response that occurs when someone develops a serious infection, and is responsible for one-fifth of all deaths worldwide. Sepsis occurs when the immune system becomes over-activated by lipid components present in bacteria, and ultimately leads to dysfunction of critical organs and death. These bacterial lipids (called pathogen-associated lipids or ‘PALs’) are transported through the bloodstream by lipoproteins, the same “vehicles” that are used for cholesterol transport. Among these vehicles, high density lipoprotein (HDL) plays a central role transporting PALs. However, HDL levels significantly decrease during sepsis, leading to reduced clearance of PALs. In our previous work, we discovered that inhibiting a specific gene called cholesteryl ester transfer protein or CETP preserved HDL levels during sepsis, suggesting that this may be a new approach to treat sepsis. We now aim to study the mechanism by which CETP regulates HDL to combat bacteria, and whether CETP inhibition will improve mouse survival in a clinically-relevant sepsis model. Completion of this project will provide new insights into the therapeutic role of CETP inhibitor in sepsis, ultimately improving the health of Canadians.
Predictive biomarkers for ovarian cancer treatment: Analysis of patient of derived xenografts under treatment at single cell resolution
Each year in Canada, around 3,000 women will be diagnosed with high grade serous ovarian cancer (HGSOC) — the most common type of ovarian cancer. Despite good responses to first line treatments for many women, it comes back as a resistant disease. Targeted treatments such as PARP inhibitors (PARPi) have made a big difference to HGSOC that is deficient in a DNA repair pathway (Homologous recombination repair), but this only benefits around 50 percent of women with HGSOC. PARPi combinations with drugs that target angiogenesis and the immune response remain under investigation. This project will investigate how chemotherapy vs. targeted therapies differentially affects the DNA damage and immune response in cancer and how effective non-chemotherapy combination treatments work, including different doses and schedules. Also, which patient might benefit from which treatment and when for example should the targeted therapies be given before or after the chemotherapy? Creating models similar to humans, we will transplant patient tumors (removed at surgery) on the skin and inside the abdomen of mice and analyze the molecular nature (at single cell level) of these tumors before/after treatment. Results of these studies will inform future clinical trials.
Air pollution as a modulator of molecular, structural, and clinical outcomes in patients with fibrotic interstitial lung disease
Interstitial lung diseases (ILDs) are serious conditions resulting in lung scarring, breathing difficulties, and a severely shortened lifespan. Air pollution is associated with ILD development and progression, but we do not understand why. This project aims to answer this question by looking at cellular and genetic changes that occur in the lungs of patients with ILD following exposure to air pollution. Using satellite-derived air pollution and clinical data from patients, we will determine if certain genes result in worse clinical outcomes when patients with ILD are exposed to more air pollution. Next, we will examine how air pollution modifies how genes are turned on or off in ILDs, through a process called DNA methylation. Lastly, we will use high-resolution imaging tools to understand how the structure of the lungs change in response to air pollution in patients with ILD. This research will help us to understand how air pollution contributes to progressive lung scarring in patients with ILD and may identify new targets for therapies to reverse lung scarring. This work will inform environmental health policies aimed at protecting vulnerable populations, including patients with ILD and other chronic lung diseases.
Medulloblastoma plasma membrane proteomics to inform optimal immunotherapy design
Brain cancer is the most common pediatric solid cancer, devastating the lives of more than 5,000 children and their families every year in North America. Current chemoradiotherapy approaches are often ineffective and cause serious side effects on the developing brain, such as permanent seizures and learning disabilities. Thus, more effective and less damaging therapies are urgently needed. Immunotherapy has been recently credentialed as a breakthrough in cancer therapy, with novel immunotherapy agents approved by the FDA for the treatment of childhood cancer. There is every indication that this progress presents the tip of the iceberg and that with continued efforts, effective immunotherapies can be developed for many currently incurable pediatric cancers. The ability for cancers to grow rapidly is in part due to the activation of specific proteins exposed on the membrane of cancer cells. The goal of immunotherapy is to target cells exposing these proteins while sparing normal, healthy cells; however, a major barrier is that most proteins on the surface of medulloblastoma cells are currently unknown. In this proposal we will identify optimal targets to ultimately develop immunotherapies against medulloblastoma.
Advancing anti-colonial implementation science and knowledge translation with the xacqanaǂ itkiniǂ (Many Ways of Working on the Same Thing) research team
xacqanaǂ itkiniǂ (Many Ways of Working on the Same Thing) is a long-term working relationship between Ktunaxa First Nation, Interior Health, University of Victoria, and University of British Columbia – Okanagan. Over the last three years, the xacqanal itkinil team developed a new approach to research that is led by Ktunaxa peoples and reflects Ktunaxa culture. We tested this approach in Ktunaxa communities by hosting a series of gatherings and land-based activities, where community members shared their vision for a healthy community. The team recently received a five-year CIHR Project Grant to build off the first phase of the partnership to work towards Ktunaxa Nation’s vision for a healthy community. We will work with community partners to co-design and implement interventions (i.e. programs, policies, practices), with the aim of transforming the culture of the health system to better serve Indigenous peoples and the wider population. This fellowship will directly contribute to monitoring and evaluating the interventions and their implementation to understand what is working well, what challenges are encountered along the way and how they are addressed, as well as how this work can be carried forward into the future.
Transforming prisons and improving health outcomes for people who use drugs: An evaluation of BC’s prison-based therapeutic community
People with substance use disorders (SUD) are more likely than those without SUD to be sent to prison and to experience negative outcomes after release. Prisons are not typically ideal environments to treat complex health issues including SUD. Therapeutic communities (TCs) offer an alternative to traditional forms of punishment, providing the environment for belonging and relationship-building, through activities such as group-based therapy, education/work, and community participation. The proposed study will evaluate Guthrie House, BC’s first and only prison-based TC which opened in 2007 at Nanaimo Correctional Centre. The study aims to identify the TC-related mechanisms of change associated with health and criminal justice outcomes, and will involve three main components: a survey with TC clients, interviews with TC and correctional staff, and linked administrative data analyses. This study has the potential to identify promising approaches to supporting people with SUD who experience incarceration. This work will add meaningfully to the policy initiatives in BC focused on reducing overdose and increasing access to SUD care.
Sex specific characterization of microRNAs in fibroadipogenic progenitors in cancer cachexia
More than 80 percent of patients with cancer encounter a severe loss of muscle and fat leading to a devastating condition called cachexia, a condition that severely affects the quality of life. Incidence of cachexia is higher in males than in females. In general, and in cancer, men have increased muscle mass while women have higher fat mass. Understanding the inherent sex-differences in disease will aid in developing effective treatment options. During muscle injury, different types of cells in muscle act in synchrony for its repair. One type of supporting cell is called as fibroadipogenic progenitors (FAPs), which provide the required growth factors for muscle regeneration. Impairment in FAPs production or function would lead to unhealthy accumulation of fat in muscle, leading to muscle wasting. The role of molecules such as microRNAs (miRNAs) contributing to this impairment remains unknown in cachexia. miRNAs are small molecules that controls expression of several genes. The current proposal aims to understand the role of sex-specific dysregulated miRNAs in FAPs and if therapeutically targeting the defective miRNAs may ameliorate muscle wasting thereby improving survival, quality of life in patients with cachexia.