Medical advances have played a fundamental role in dramatically increasing life expectancy in Canada and around the world. This has created challenges for the health-care system as a number of diseases exhibit increased incidence with age. Two examples include Alzheimer’s disease (AD) and cancer; cancer is now the leading cause of death in Canada. Continued research into the causes and progression of the disease is sure to provide advances in our ability to treat and eventually prevent the disease, with great benefit to our society and economy. The overall goal of Dr. Tim Storr’s biomedical research program is to develop new chemical tools to diagnose and treat the disease.
Storr’s team is focusing their research efforts in two areas: metal-overload diseases, and cancer. Many metal ions are essential to our existence, yet under certain conditions can become toxic. The team is currently studying the role of excess metal ions in the development of AD and Wilson’s disease (WD). The increased incidence of AD, and the lack of effective treatment strategies, underscores the pressing need for research into the causes, and the development of new therapeutic options. Storr’s team is investigating a new approach to AD treatment in which drug molecules are activated in the presence of excess metal ions, allowing for selective therapy. At the same time they are applying this treatment strategy to WD, a genetic metal overload disease in which excess metal ions accumulate in the liver. The overall goal is to bring forward new treatments for metal overload diseases that are generated at the site of need and only when excess metal ions are present.
Storr’s team is also applying chemical tools to cancer by developing imaging agents that allow for the early detection of the disease, and the ability to monitor treatment regimens. This information is key to a successful patient outcome, and the group is currently investigating differences in the energy needs of normal and cancerous tissue. Working at the interface of chemistry, biology, and medicine, this research promotes investigation across disciplines towards the design and testing of innovative disease treatments.
Pathogenic bacteria, such as P. aeruginosa, E. coli, and K. pneumonia, can cause serious infectious diseases such as pneumonia, urinary tract infections, and diarrhea. These bacteria are becoming resistant to many of our commonly used antibiotics and have been spreading rapidly over the past decade. Antibiotic-resistant bacteria are a serious threat to Canadian and global health, and new strategies are needed to combat them.
Groups of enzymes called beta-lactamases confer antibiotic resistance to the bacteria by allowing them to destroy beta-lactam antibiotics such as penicillin. Moreover, ongoing changes in bacterial beta-lactamase genes in nature are producing more potent enzymes to destroy our newest antibiotics.
Dr. Nobuhiko Tokuriki’s research will study the ways that beta-lactamase enzymes change. His team will combine experiments in the laboratory to identify mechanisms of change with detailed studies of enzyme function so they can develop ways to block their activity. The information obtained in this research will ultimately be used to develop novel, persistent, and sustainable antibiotics and inhibitors against pathogenic bacteria.
Cancer deaths are driven by two key biological processes: metastasis and treatment resistance. Although these processes are extensively studied as unrelated occurrences, evidence of shared signaling networks suggests common genetic or adaptive events. These pathways will change a therapy-responsive tumour to a resistant and lethal tumour. This occurs in prostate cancer where strategies used to kill tumours induce adaptive responses promoting the emergence of treatment-resistant tumours prone to metastasize. There is limited study of linkages between metastasis and treatment resistance, and Dr. Amina Zoubeidi’s research program will address an important knowledge gap in our understanding of aggressive tumour behavior in prostate cancer. The hope is that this research will translate into novel therapeutic development for prostate and other human cancers.
Zoubeidi’s work will be facilitated by her recent development of novel cell lines and xenograft models of prostate cancer that are resistant to a new generation of the AR pathway inhibitor drugs MDV3100 and abiraterone. These drugs, while recently introduced as therapeutics for patients with castration-resistant prostate cancer, offer survival gains of only four months and promote MDV- or abi-resistance. Zoubeidi has observed that MDV-resistant tumours metastasize whereas the castration-resistant tumours from which they were derived are non-metastatic. These observations suggest that tumours acquire metastatic traits in parallel with drug resistance.
Zoubeidi’s research program will focus on identifying common molecular mechanisms that elicit both metastasis and resistance to this new generation of prostate cancer drugs. Because tumour invasion and resistance dictate treatment outcome, pathways identified with this approach will represent relevant targets that can be inhibited singularly or jointly as more effective therapy. The research program is organized under three themes: the role of sustained AR activation in these processes; mechanisms associated with acquired EMT and their abilities to elicit treatment resistance; and the emergence of cancer cell “stem-ness” as a common mechanism driving treatment resistance and metastasis.
Individuals 65 years of age and older constitute the fastest growing age group in Canada. With natural adult aging, the neuromuscular system (the muscles of the body and the nerves that supply them) undergo degenerative changes that are characterized by reductions in strength and power due to decreased muscle size. This age-related muscle weakness and overall decline in muscle function is referred to as sarcopenia. Sarcopenia not only interferes with tasks as lifting and carrying groceries, navigating stairs, and performing smooth complex movements, it is highly linked to physical disabilities and risk of falls. Sarcopenia is caused by a decrease in the number and function of motor units (MU), which consists of a single nerve branch and all of the muscle fibres it supplies. During the aging process, some of the MUs die off, while other MUs change structurally to compensate. As a result, there are fewer MUs present, but each one supports more muscle fibers. This MU remodeling process is a compensatory mechanism that acts to maintain muscle strength until a critical threshold is reached and strength decreases at an accelerated rate, usually by the eighth decade of life.
To understand the underlying biological mechanisms of MU remodeling, Dr. Brian Dalton is using a technique called single-unit microneurography. This research tool uses tiny electrodes inserted through the skin and into a peripheral nerve to stimulate and record signals from individual MUs. Using this technique, he will measure the integrity of functioning MUs in aged adult volunteers to determine if MU remodeling impairs neuromuscular function and muscle performance in the older adult. This work will help build a more comprehensive understanding of the neuromuscular system, specifically the process of sarcopenia and how it impacts natural adult human aging. The information gained from this study will aid in the design of functional training programs to improve and maintain muscle function — and quality of life — in older adults.
Diabetics are two to four times more likely than non-diabetics to suffer a stroke during their lifetime, and their prognosis for recovery from stroke is poor. Diabetes is known to negatively affect blood vessels throughout the body, including the eye, heart, kidney, and limbs, leading to a heightened risk of stroke in diabetics. Poor circulation and peripheral nerve damage can lead to blindness, hearing loss, foot injury and amputation. High blood pressure is common in diabetics and increases the risk of heart disease and stroke. However, little is known about how the vascular changes associated with diabetes affect the brain and contribute to poorer recovery of function following stroke.
Dr. Kelly Tennant's research will determine why diabetics suffer from greater impairments following strokes. She will monitor changes in neurons and blood vessels over time following a stroke in diabetic mice and assess the relationship between these changes and recovered use of the forelimb. Dr. Tennant will employ cutting edge in vivo imaging technologies such as intrinsic optical signal, two-photon, and voltage sensitive dye imaging, combined with behavioural testing of forelimb function.
These experiments will shed light on how neurons and blood vessels of diabetics respond differently to ischemic stroke and how these differences contribute to poor behavioural recovery in diabetic stroke survivors. This research will aid understanding of the greater impairment caused by stroke in diabetic patients and lead towards development of treatments that ameliorate the negative effects of diabetes on the brain.
The cilium is an extension on most cells and tissues that works similarly to a television antenna, in that it receives signals from the environment. When a mutation disrupts the function of cilia, cells no longer receive the proper environmental input. Mutations in cilia proteins have been identified in patients with clinical ailments such as blindness, obesity, diabetes and polycystic kidney disease; some are also found in syndromes encompassing all or most of these disorders. Although some of these syndromes affect entire families, the molecular and cellular causes of these disorders have not been identified or characterized; for this reason there are no therapies available. Dr. Victor Jensen aims to study and identify novel cilia genes that are associated with multiple disorders, including blindness and obesity. These results will provide essential information about the association between disease and different genes, as well as the function of cilia. This unique approach to gene discovery and characterization was developed in the laboratory of Dr. Leroux, and has already led to the discovery and understanding of numerous disease genes, including those associated with the multi-systemic Bardet-Biedl syndrome. Dr. Jensen’s research work is therefore aimed at providing novel insights into the nature and function of disease genes, a step that will eventually lead to improved treatments or prevention of common human medical ailments.
Lung cancer is one of the largest health burdens worldwide: in Canada alone, lung cancer causes more cancer-related deaths than breast, colon, and prostate cancers combined. Smoking cessation programs have been highly successful, and the population of former smokers in Canada is well over seven million. Unfortunately, while quitting smoking is a proactive step, former smokers are still at risk for developing lung cancer. This cancer risk in former smokers will remain one of Canada’s most significant health concerns for the next 50 years. The molecular mechanisms responsible for the development of lung cancer in former smokers are not known. Recent studies have shown that although the majority of smoking-induced genetic damage returns to normal after smoking cessation, some genes are permanently damaged and never return to the pre-smoking state. Some of these irreversible genes are likely those that act as the gatekeepers for cancer development. Dr. Ewan Gibb’s research project will identify the genes in former smokers which do not return to normal after smoking cessation. He will be using integrative genomics to compare samples from former smokers with cancer and those without. This information will help Dr. Gibb understand why some former smokers go on to develop lung cancer while others remain cancer-free despite similar changes in lifestyle. This set of irreversibly damaged genes can serve as novel targets for anticancer therapies or may be developed as diagnostic markers for early detection of lung cancer while therapies are still effective.
Each human cell contains instructions — in the form of genetic material or the genome — to direct its growth, function and death. The genome is made up of three billion molecules called nucleotide pairs, which are joined in a specific sequence. Sometimes the nucleotide sequence in a cell’s genome can become altered, or mutated, and these mutations can lead to changes in the cell that cause cancer. The spread of cancer cells from the primary tumor is known as metastasis. Relatively little is known about the mutations in the genome that create, control and direct metastasis. Next-generation sequencing allows researchers to rapidly “read” the sequence of the three billion nucleotide pairs in the genome of cancer cells. Using this technology, Dr. Jill Mwenifumbo aims to identify the sequence mutations that are unique to, and perhaps essential for, colorectal cancer metastasis. Ultimately, discovering the genetic mutations that drive metastasis will help identify potential drug targets, which will lead to more effective treatments for this disease. Given that colorectal cancer is the second leading cause of cancer death in Canada, effective treatment has enormous potential to improve personal and population health.
Type 2 diabetes currently affects 2.5 million Canadians. Elevated blood cholesterol levels increase the risk of developing diabetes. Scientists are starting to understand the molecular basis of diabetes and have recently discovered that a deficiency of the ABCA1 molecule, a transporter that removes cholesterol from cells, leads to the accumulation of cholesterol in the insulin secreting-beta cells in the pancreas. This cholesterol accumulation leads to impaired insulin secretion and contributes to diabetes. Therefore, influencing the levels of ABCA1 molecules in beta cells may help control both cholesterol and diabetes. The objective of Dr. Nadeeja Wijesekra’s research is to discover new ways to regulate ABCA1 levels in beta cells in order to improve beta cell function and survival. Her project involves the use of small molecules called microRNAs to regulate ABCA1 levels in mouse beta cells. She will identify specific microRNAs that regulate ABCA1 levels in beta cells and determine how they influences beta cell function by measuring insulin secretion and changes in cholesterol levels. Furthermore, these microRNAs will be used in diabetic mouse models to assess whether their disease condition can be improved. Since increased ABCA1 has been shown to have a positive impact on beta cell function, finding ways to increase ABCA1 levels in these cells may be helpful in ameliorating beta cell defects present in diabetes. Thus these studies are the first to outline a therapeutic strategy to modulate cholesterol in beta cells in order to improve whole body glucose homeostasis.
