Program: Trainee

Role of the Histone Acetyltransferases p300/CBP in Brown Adipose Tissue Adaptive Thermogenesis

Obesity is rising in Canada at an alarming rate, which is bad for our healthcare system because it results in diseases like heart attacks and diabetes. Although eating less and exercising more can reduce weight, these lifestyle changes can be difficult to maintain, prompting interest in finding ways to ramp up the calorie-burning processes in the body to promote weight loss. Brown adipose tissue (BAT) is a kind of fat that is found in both humans and mice. Unlike white adipose tissue, BAT is specialized for calorie burning rather than storage. We don't know exactly how the body controls how much BAT it makes, how it turns BAT on for burning energy to control body weight, or why some people lose their BAT with age.

One possible way these processes might be controlled is via proteins that 'open' and 'close' DNA within BAT to turn key calorie-burning genes on and off. Proteins that close DNA within BAT can worsen obesity by blocking BAT development, so the body can't burn as many calories. We are interested in how proteins that 'open' DNA (specifically, a pair called p300 and CBP) in BAT can influence energy expenditure.

To find out whether p300/CBP activate BAT calorie burning, we will induce obesity in mice that have p300/CBP working within their BAT, and in mice without these proteins. We expect mice missing p300/CBP will also have problems making BAT, so they will also be unable to burn energy using this tissue – resulting in the development of obesity and diabetes.

 

Development of a novel intranasal oligonucleotide delivery approach for Huntington disease

Huntington disease (HD) is a progressive brain disorder affecting movement, mood, and cognitive skills, caused by inheriting a mutated copy of the huntingtin gene. This results in the production of a mutant huntingtin protein (mHTT) that is toxic to critical nerve cells in the brain. Reducing mHTT using specialized pieces of DNA, called antisense oligonucleotides (ASOs), should slow or prevent disease onset. However, ASOs cannot reach the brain when delivered into the bloodstream, due to the presence of the blood-brain barrier (BBB), and thus require surgical injection into the brain or the cerebrospinal fluid (CSF) that bathes the brain.

Intranasal administration is a delivery method that bypasses the BBB and can deliver large therapeutic molecules to the brain. Here, we propose a strategy to deliver ASOs to the brain using nanoparticle (NP) carriers we have developed which encapsulate ASOs, enhance their ability to cross cells membranes and penetrate the BBB. We will intranasally deliver these ASO NPs in HD mice to reduce mHTT in the brain. This approach represents a novel non-invasive means for improving delivery and distribution of ASOs into the brain, and advancing development of HD therapies.

Findings will be shared with the scientific public through publications and conference presentations, and to the general public and HD patients through educational seminars/workshops in our lab.

 

Investigating the impact of evolving cannabis access and use on high-risk drug use behaviours and addiction treatment

Cannabis remains the most widely produced, trafficked and consumed illicit drug worldwide, and at this time Canada and many other countries are implementing alternative regulatory approaches to cannabis. While research on cannabis has traditionally focused on the harms of cannabis use, an emerging body of evidence suggests that cannabis use can also alter high-risk drug practices, such as reducing cocaine use, opioid use and associated overdose. Much of this work suggests that cannabis is often used as a substitute for harder drugs of abuse which may have important implications for health policy responses to the current opioid epidemic in British Columbia.

However, this evidence has been primarily cross-sectional and ecological in nature, and lacking are rigorous longitudinal studies unpacking the precise impacts of cannabis use and evolving cannabis policy on the development of high-risk drug use behaviours. Further, the impacts of cannabis use on HIV and addiction treatment outcomes remains unclear. In light of the recent legalization of non-medical cannabis, identifying the impacts of cannabis on high-risk substance use and drug treatment outcomes will be important for informing clinical and public health practice, as well as policy.

Prevalence, patterns, and harms associated with the co-injection of illicit opioids and crystal methamphetamine

Crystal methamphetamine use is associated with a wide array of physical and social harms. In spite of this, its prevalence is rising in many parts of North America. Several small studies have suggested increasing rates of co-injection of methamphetamine and opioids, though no research has focused on the specific harms associated with this trend. In Vancouver, preliminary reports have noted a similar pattern, in a context where fentanyl has become the most widely used form of illicit opioid.

In this study we propose to use a prospective cohort of people who inject drugs to ask how trends in the co-injection of methamphetamine and opioids are changing over time, and to explore the health consequences associated with this pattern of substance use as it relates to overdose risk and response to treatment.

Answering these questions will provide insight into important changes in the evolving epidemiology of substance use, and will provide information on potential implications. An appreciation of these changing patterns is not only crucial in developing evidence-based harm reduction and treatment strategies, but also in understanding how to devote treatment resources appropriately in the fight to reduce opioid-related deaths.

Examining how contextual factors and health equity considerations shape the implementation of an internet-based testing service for sexually transmitted and blood-borne infections

This study will examine how organizations are able to roll-out and improve GetCheckedOnline (GCO), an internet-based testing service for sexually and blood transmitted infections currently available in British Columbia.

Using the research approach of institutional ethnography, this study aims:

  1. to learn what it takes to implement and expand GCO in fair and sustainable ways, and
  2. to speak to healthcare and community stakeholders in British Columbia to understand the contextual obstacles and opportunities that have shaped the implementation of GCO.

This study's findings will help to inform how GCO can be improved to expand the service to new locations in British Columbia and potentially to the healthcare system in Toronto, Ontario. More generally, this project will offer insights into how sexual health services are implemented and how to promote the equitable growth of digital health interventions.

Investigating noncoding RNA networks in hematopoiesis

The genetic material of cells is DNA. The popular notion in biology for a long time was that DNA makes RNA which in turn makes proteins. But over the past two decades, research has shown that not all types of RNA are converted to protein. These RNAs which do not make (or do not code for) proteins are called noncoding RNAs. Long noncoding RNAs (lncRNAs) belong to one of the classes of noncoding RNAs. Based on various studies, we know that lncRNAs are crucial during different biological contexts including embryonic development as well as disease. The importance of lncRNAs in blood stem cells and blood cancer is not yet studied in detail. We will study how lncRNAs can help blood stem cells to either remain as stem cells (maintain stemness) or convert into different blood cell types (differentiate) and how they control the blood stem cells from forming cancer.

One of the very recently studied modes of action for lncRNAs is the binding of long noncoding RNAs to other class of noncoding RNAs called microRNAs and blocking the action of microRNAs. By using several techniques, we will systematically decipher lncRNAs acting by the microRNA mechanism to the blood stem cells in maintaining stemness or differentiation. The knowledge from this project will improve our understanding of the biology of blood stem cells and can be helpful in future for treatment of disorders of the blood system, bone marrow failure and cancer.

Identification of IL1RAP as a novel oncoprotein and therapeutic target in Ewing sarcoma

Ewing Sarcoma (EWS) is an aggressive form of childhood cancer that occurs on bone and soft tissue. Although conventional cancer therapeutic strategies, such as chemotherapy, radiation and surgery, have improved survival in patients with localized EWS tumours, they are ineffective for patients with metastatic disease. In addition, conventional chemotherapy is often toxic and carcinogenic, which carries short- and long-term toxicities. In the past few years, immunotherapy has been promoted as an effective means to prolong survival or eliminate tumor cells in patients with specific cancers.

However, effective immunotherapeutic strategies for EWS have not yet been described. Identification of highly specific cell surface markers of tumor cells is critical for developing targeted immunotherapy strategies. We have identified IL1RAP (Interleukin 1 receptor accessory protein) as a cell surface protein that is highly expressed in EWS in comparison to normal tissues/organs, and that is important for tumorigenesis in this disease. In this project, we aim to develop immunotherapeutic strategies by targeting IL1RAP in human EWS, while also delineating the key mechanisms mediating the tumor-promoting function of this protein.

End of Award Update – March 2022

Most exciting outputs

During the Health Research BC / Lotte & John Hecht Memorial Foundation award period, my work in Dr. Poul Sorensen’s lab identified IL1RAP (Interleukin 1 receptor accessory protein) as a cell surface protein that is highly expressed in Ewing sarcoma, but minimally expressed in pediatric and adult normal tissues, nominating it as a promising immunotherapy target. Our mechanistic studies show that IL1RAP maintains cyst(e)ine and glutathione pools in Ewing sarcoma, which are vital for redox homeostasis and metastasis.

To therapeutically target IL1RAP, we have collaborated with Dr. Dimiter Dimitrov of the University of Pittsburgh to develop IL1RAP binders via phage-display biopanning. We identified highly specific IL1RAP binders, one of which has been engineered into a humanized IgG1 antibody. This antibody can induce antibody-dependent cellular cytotoxicity (ADCC) in Ewing sarcoma cells. Moreover, in collaboration with Dr. Rimas Orentas of the Seattle Children’s Hospital, we have developed IL1RAP CAR (chimeric antigen receptor) T cells, which can mediate potent tumor cell killing in vitro, and we are currently optimizing the IL1RAP CAR for higher in vivo efficacy in mouse models. Some of these findings have been published in Cancer Discovery.

With regard to the mechanistic studies of the pathobiological function of IL1RAP, i.e. IL1RAP maintains cyst(e)ine and glutathione pools that promote Ewing sarcoma metastasis, we recently published a review article on this topic in Trends in Cell Biology, a Cell Press journal.

Impacts so far

Based on our findings, we have filed a patent for IL1RAP CAR-T cell therapy in human cancers.

Potential future influence

Based on our findings, we may initiate clinical trials in the near future to target IL1RAP with immunotherapeutic strategies, including highly specific chimeric antigen receptor (CAR) T cells and antibody-drug conjugates.

Next steps

We aim to develop various immunotherapeutic strategies to target IL1RAP in human cancers, including highly specific chimeric antigen receptor (CAR) T cells and antibody-drug conjugates.

Useful links

 

The impact of opioid agonist treatment on antipsychotic adherence among justice-involved patients in British Columbia

Substance dependence and mental illness frequently co-occur, presenting challenges to treatment providers and increasing the likelihood of suicide, drug overdose, and criminal justice involvement. Assessment and treatment of concurrent disorders (CD) have been identified by police, health professionals, and the Auditor General as urgent priorities in BC, and leadership in the treatment of CD is integral to the mandate of the Provincial Health Services Authority. 

Despite well-documented personal and public risks associated with schizophrenia and opioid dependence, little research has examined the combination of these disorders. Medications, including methadone and antipsychotic drugs, are the first line treatments for patients with these diagnoses. Recent studies, including research conducted in BC, have revealed low levels of adherence to these prescribed medications, leading to increased risks of violence, property crime, and mortality. 

Researchers investigating HIV/AIDS have shown that when opiate dependent patients are adherent to methadone they are also more likely to follow their HIV/AIDS treatment. This research will investigate whether methadone adherence similarly increases adherence to antipsychotic treatment and leads to superior outcomes for patients diagnosed with both disorders. 
 

Incorporating practical, high-intensity interval training (HIIT) into the workplace: Examining the impact on physiological and psychological health, absenteeism, and work productivity

Among office workers, physical activity has been shown to have the potential to improve absenteeism, work productivity and psychological and physical health.

Dr. Stork’s research will incorporate physical activity into the workplace using high-intensity interval training (HIIT) – short-duration exercise that consists of multiple brief, high-intensity efforts, separated by periods of rest.

In Phase 1, physically inactive office employees will undergo an 8-week HIIT program of either one daily HIIT session completed during lunch break, or brief exercise bouts dispersed throughout the workday as 'exercise snacks.' Phase 2 will deliver an 8-week optimized HIIT program designed for sustainability based on a process evaluation of Phase 1. Dr. Stork will measure physical and psychological health, physical activity behaviour, absenteeism and work productivity immediately and up to six months following the program.

The HIIT programs will be implemented in Kelowna's Landmark Centre office towers. Community partners will be engaged early on in the research process to work together to successfully ensure that the program is evidence-based and implemented in a sustainable manner that adequately serves the community. The HIIT programs implemented will undergo a process evaluation to better understand the barriers and facilitators and to optimize and tailor the design and delivery of future programs.

Cerebrovascular burden and cognitive impairment after spinal cord injury

Spinal cord injury (SCI) is a complex pathophysiology, characterized not only by paralysis but also severe autonomic cardiovascular dysfunction. After SCI, strokes are 300 – 400% more likely to occur compared to non-disabled individuals.

One potential explanation for this is autonomic dysreflexia (AD), a life-threatening condition whereby persons experience sudden, transient episodes of high blood pressure. Such volatile swings in blood pressure in individuals with SCI result in structural and functional changes within peripheral blood vessels and lead to the deterioration of peripheral organs, including the brain. In the general population, chronic hypertension is a key risk factor for cerebrovascular dysfunction (increased stroke-risk and cognitive impairment). However, it is currently unclear whether the cumulative load of AD plays a similar role in cerebrovascular and cognitive impairment in persons with SCI.

Using the latest technological advances in magnetic resonance imaging, Dr. Nightingale’s research will examine differences in the structure and function of micro-vessels in the brain between two groups of SCI participants with different durations of SCI (and thus AD exposure), relative to an able-bodied age-matched control group. The results of this research will lead to a better understanding of AD in SCI individuals, and potentially improve treatment to better prevent the occurrence of stroke.