Research Pillar: Biomedical

Non-invasive Neuroprosthesis for Cardiovascular Recovery Following Spinal Cord Injury

Spinal cord injury (SCI) not just causes paralysis but also more devastating issues such as impaired blood pressure (BP) and heart rate regulation, which are among the leading causes of illness and death among this population. The individuals with SCI above the mid-thoracic level commonly suffer from highly labile BP that rapidly reaches alarmingly high and low levels within the same day. These extreme BP fluctuations often result in seizures, ruptured brain blood vessels and even death. Hence it is not surprising that the individuals with SCI rank improving heart and blood vessel function among the highest priorities for recovery, even higher than regaining the ability to walk again.

The goal of this proposal is to test the potential of non-invasive spinal cord stimulation (delivered through skin) to promote blood pressure control in a rat model of SCI. Our laboratory's pilot experiments have already demonstrated that non-invasive stimulation is feasible and effective in humans with SCI. Present proposal will allow us to thoroughly understand the underlying mechanisms and enable widespread clinical use of spinal cord stimulation in improving quality of life of individuals with SCI.

Investigating the Role of MicroRNAs on Granule Cell Development during Mouse Cerebellar Development

The cerebellum is a complex region of our brain involved in the coordination of our movements and cognition. Evidence shows that cerebellum is involved in several brain disorders such as ataxia (inability to move properly), autism, and medulloblastoma (the most prevalent brain tumor in children). The cerebellum is made of different cell types. Among them, the most numerous cell type, the granule cells, contribute to many crucial cerebellar functions. Indeed, an uncontrolled division of granule cells results in the most common form of pediatric brain tumor, the medulloblastoma. To understand the basis of cerebellum-related diseases and finding effective treatments, we need to study cerebellar development.

In my project, I will study the role of special regulatory molecules called microRNAs, which control gene activity in the developing cerebellum. Using modern cellular, molecular, and computational techniques, I will find a subset of microRNA molecules and their partner genes, which contribute to the normal development of granule cells in the developing cerebellum. Results of this work will provide useful and basic knowledge for scientists who study disorders of the brain, which have their roots in cerebellum development.

Assessing Small Airway Disease Heterogeneity in Asthma to Identify Novel Therapeutic Targets

Asthma is a serious public health issue in Canada and in the world, affecting more than 300 million people globally. To date, clinical trials have established that current treatment strategies for asthma can relieve patient symptoms, but none are able to reverse the disease process. It is known that in asthmatic lungs, the airways -tubes that allow air to flow in and out of the lungs for breathing – are continually injured and scarred in a process called fibrosis. The smallest airways in the asthmatic lung are the main sites of fibrosis and thought to have the greatest contribution to disease symptoms; however, current methods used to assess asthma are unable to provide information on the smallest airways.

Assessing these smaller airways could provide new ways to develop drugs to resolve the scarring that occurs in asthma. In this project, we will use new, more powerful imaging methods to determine the contribution of the small airways scarring in asthma and to identify the genes involved in this process. We will then develop laboratory models of the disease using patient lung cells that may be used in the future to develop new drugs to target the genes involved and resolve the scarring and blockade in the airways of asthmatic patients. The potential new drugs that will be found in this research will help to relieve the burden of asthma in BC.

 

HEARTBiT: A novel multi-marker blood test for management of acute cardiac allograft rejection

Patients receive heart transplants as a life-saving measure after heart failure; thus, ensuring the success of the transplant is of utmost importance. Rejection is a primary cause for heart transplant failure, and consequently, heart transplants are monitored at least 12 to 15 times within the first year of operation. However, current monitoring requires biopsies, a surgical procedure which requires repeated sampling of the heart muscle. This procedure is invasive, expensive, and stressful to patients. Replacing the biopsy with a simple blood test can greatly improve patient quality of care and reduce healthcare costs.

Therefore, my goal is to develop a new blood test to monitor rejection following heart transplants. Using sophisticated computer algorithms, our group discovered molecules in the blood that can discriminate between patients who have rejected their heart transplants and those who have not. My goal is to develop a blood test to precisely measure these molecules. Also, I will study these molecules for their biological role in heart rejection process by examining immune cells and damaged heart cells found in biopsies. Accomplishing these research goals will produce a valuable clinical tool that can diagnose rejection in a fast, accurate, cost-effective, and minimally invasive manner.

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 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

 

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.

Microbial control of gut environment in IBD

Gut health is closely connected to our microbiota, a unique, constantly evolving, group of trillions of bacteria that live in our bodies. Gut microbes produce compounds that are absorbed into our blood, providing nourishment and also affecting the gut environment. The digestive tract is composed of many different local areas, called habitats, in which physical and chemical properties such as water availability, salt concentration, acidity or temperature are tightly controlled by human-microbe interactions. These habitats are dramatically changed by inflammatory bowel disease (IBD) and in return affect which microbes can survive within them. Despite the importance of the gut environment to IBD, we know little about its effects on the gut microbiota and on the progress of the disease.

I will use a combination of cutting-edge experimental and computational techniques to study the connection between the gut microbiota, the gut microenvironment, and IBD. My laboratory will study tissues from IBD patients to identify what aspects of the gut environment and microbiota can predict flares and remission. We will also study isolated bacteria and study how they respond to, as well as modify, their environment in a mouse model of IBD. This research will lead to health and economic benefits for Canadians, by developing microbiota based therapies for diseases of the digestive tract that affect millions of Canadians.