Year: 2019

Protein-energy wasting: prevalence and treatment outcomes among patients with advanced chronic kidney disease in British Columbia

People with or approaching kidney failure requiring dialysis often develop protein-energy wasting (PEW), which is characterized by loss of body stores of protein and energy fuels, and is associated with increased risk of death, heart disease, infections, and poor quality of life. The extent of PEW, its consequences, and its management have not been previously characterized among kidney patients in Canada, yet nutritional management remains a top research priority from the patient perspective.

Utilizing an existing database of chronic kidney disease patients in BC, the aims of the proposed study are:

  1. to determine the number and characteristics of adult kidney patients with PEW in BC, using several nutritional parameters and their changes over time to define PEW;
  2. to assess the impact of PEW treatment with nutritional supplementation (according to the BC Renal Nutritional Supplement Policy) on outcomes, including death, hospitalizations, nutritional lab parameters, and patient-reported functional status.

This research will:

  1. identify patients at risk of adverse outcomes from PEW in order to improve treatment policy and resource allocation, and
  2. inform future studies of dietary/self-management strategies for kidney patients

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

 

Health, work and society: Improving health economic evaluations

Decision makers need to decide how to best allocate limited societal and healthcare resources to fund different healthcare services. Health economic evaluation is a tool commonly used to inform these types of funding decisions; however, which costs to consider in economic evaluation can have a significant impact on the resulting funding decision. A societal perspective considers costs within the formal healthcare sector (e.g., physician, hospital and drug costs) as well as costs outside the healthcare sector (e.g., work productivity costs of patients and their family caregivers). Existing health economic evaluations have largely ignored patient and caregiver work productivity costs mainly due to the limitations in current measurement methods.

My program of research will focus on the development of methods that will provide accurate estimates of patient and caregiver work productivity costs. These methods will then be applied and tested in an economic evaluation of new treatments for recurrent Clostridium difficile infection. Ultimately, my research findings will help improve health economic evaluations for other diseases, leading to better healthcare decision making in BC, Canada and beyond.

End of Award Update – March 2024

 

Results

My research program has provided practical recommendations on how to measure, analyze and present work productivity loss among patients and their caregivers in clinical trials.

 

Impact

There are increasing research interests in measuring the impact of health care interventions on work productivity loss by following the practical recommendations developed during my award period.

 

Potential Influence

There will be consensus methods for measuring, analyzing, and presenting work productivity loss results across studies. This will improve the comparability between studies.

 

Next Steps

More related articles will be published in journals and presented at conferences. Workshops will be organized to teach on the methods of measuring, analyzing, and presenting work productivity loss.

 

Useful Links

www.thevolp.com

Investigating the Biomechanical Mechanism of Concussions in Sports

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.