Resistance to cancer and infectious diseases relies on complex responses in our immune system. Natural killer (NK) cells provide a first line of defence, recognizing and killing infected and tumour cells, while sparing normal cells. NK cells use an intricate system of proteins, found on their surface, to either activate or inhibit their “natural killer” activity. However, the mechanisms by which these proteins induce this action are not completely understood. Dr. Valeria Alcón is studying two cellular proteins (CD72 and CD100) that are involved in the activation of several immune cells to determine how these proteins regulate natural killer cell activity. She is also examining how NK cells interact with other immune system cells to induce immune responses. Her research could explain how to activate natural killer cells, leading to the development of more effective treatments for infectious disease and cancer.
Program: Trainee
Molecular mechanism of Prp24-mediated U4/U6 formation
Messenger RNA (mRNA) is a single-stranded molecule of ribonucleic acid found in the nucleus of cells that transmits the genetic information needed to produce proteins. This production process involves “splicing” of the mRNA, whereby non-protein coding sections are removed. The splicing process must be precise as errors can result in genetic disease. For example, mutations in BRCA1, which are implicated in some breast cancers, and mutations in SMN2, which cause spinal muscular atrophy, result in defective splicing of their messenger RNA. To minimize mistakes, the cell regulates splicing. However, many of the details of this process are unclear. Dr. Kelly Aukema is studying the molecular mechanisms involved in splicing, using fluorescence resonance energy transfer (FRET) – a cutting-edge technique for measuring interactions between two molecules. She will use FRET to investigate the structural RNA changes of the molecular machinery that carries out splicing. This knowledge should ultimately lead to a better understanding of, and more effective treatments for, splicing-related diseases.
Molecular analysis of Mycobacterium tuberculosis protein phosphatase
Tuberculosis (TB) causes about eight million new infections each year and up to three million deaths. Already one of the leading causes of death world-wide, the number of deaths from tuberculosis continues to increase as new, antibiotic resistant strains and co-infections linked to HIV emerge. A third of the world population has been exposed to Mycobacterium tuberculosis, the bacteria that cause TB. The disease is spread from one person to another, when someone with TB coughs or sneezes and people nearby breathe in the bacteria and become infected. TB most commonly affects the lungs, attacking and destroying tissue, but also can spread to other parts of the body. Despite its prevalence and long history, little is known about the survival of the pathogen in macrophages. Dr. Horacio Bach is studying how proteins secreted by TB bacteria enable them to evade the body’s immune defenses and survive to multiple inside host cells. This research should help explain the cellular mechanisms involved in causing the disease, and could lead to new therapies for controlling tuberculosis bacterial infections.
Perceptions of Health Care Providers about Integrative Breast Cancer Care: A Pilot Study
Complementary therapies are a diverse set of treatment approaches that fall outside of mainstream medicine. The majority of cancer patients – especially those with breast cancer – use a form of complementary therapies. While there is growing evidence that some of these therapies can contribute to effective cancer care, their use has not become part of standard cancer care. Patients often research complementary care options and investigate ways of integrating them in their treatment plan, without discussing these approaches with conventional health care providers. This can lead to poorly integrated care, which raises concerns about potential toxicities, adverse reactions and patients engaging in therapies with little therapeutic value. Alison Brazier is researching health care providers’ perceptions of the factors that either serve as barriers or facilitate an integrative approach to breast cancer care. Alison is conducting a series of in-depth qualitative interviews with health care providers and women living with breast cancer in four Canadian cities. She is also developing a survey instrument, to be used in a large national survey, which examines the attitudes and knowledge of complementary and conventional health care providers about integrative cancer care. The results of this study are aimed to enable a more integrative approach to cancer care in Canada that provides safer, more effective and more comprehensive cancer care.
Investigation of the impact of HLA genetic diversity on HIV sequence evolution and clinical correlates of HIV disease
One of the major challenges facing HIV treatment and vaccine design is the virus’ capacity to mutate extremely rapidly in response to a changing environment. The course of HIV infection within a given individual is characterized by a constant, dynamic evolution of the virus. It is now appreciated that a wide range of host genetic factors influences the course of HIV infection and disease progression. The proposed research project seeks to investigate the effects of genetic variation within specific genes of the human immune system (called the “”Major Histocompatibility Complex”” or “”MHC”” genes) on the clinical course of HIV infection. The results of this project will help us gain a more detailed understanding of the multiple genetic factors that affect the course of HIV infection, and help bring us closer to the potential incorporation of human genetic information into the clinical management and treatment of this disease. In addition, this research will be of relevance in the continuing efforts to develop a vaccine against HIV. Research such as this will help us develop and implement strategies for clinical management of HIV/AIDS and will therefore ultimately be of benefit to individuals living with HIV.
Investigation of the factors secreted by feeders used in the maintenance of human embryonic stem cells
Embryonic stem cells can continually replicate themselves and also have the capacity to differentiate into other types of cells. Consequently, stem cells have the potential to replace damaged tissues in our bodies, which could revolutionize the treatment of degenerative diseases and traumatic injuries. Currently the production of human embryonic stem cells in the lab setting requires use of “feeder cells” from mice in order for the stem cells to grow. Having to depend on feeder cells limits large-scale production and also could introduce unacceptable risks in clinical applications. Dr. Nicolas Caron is investigating which proteins from feeder cells nourish stem cell growth. His goal is to develop a feeder-free culture that would be equally effective for growing stem cells. This research could lead to the development of cell-based therapies for genetic diseases, and support research into ways of shifting from organ, to cell-based transplants.
Alterations in cellular signalings in human diabetic vasculature contribute to diabetes-associated cardiovascular complications
The prominence of diabetes as a risk factor for cardiovascular complications has been rising in recent years, largely attributed to increased longevity combined with a non-active lifestyle and an unhealthy diet. Up to 80 per cent of deaths in diabetic patients are related to cardiovascular disease. The cardiovascular complications associated with diabetes occur when blood vessel walls thicken in response to changes in intracellular signaling within the vascular tissue. Dr. Ada Chung is identifying the underlying molecular mechanisms responsible for accelerated thickening of vessel walls and poor blood vessel formation, which lead to vessel blockage, hypertension, angina and other cardiovascular complications in patients with diabetes. Understanding these molecular mechanisms may be beneficial to medical innovations in diagnosis and treatment that can delay the onset and slow the progression of diabetes and its related cardiovascular complications.
The Zot system of intercellular tight junction regulation
In order to improve the effectiveness of drugs taken orally (by mouth), researchers need to understand how the lining of the gut (intestinal epithelium) functions to block drugs from being absorbed into the circulation system. The lining provides a protective barrier that selectively allows certain molecules to flow across it. While larger molecules typically are blocked from crossing the intestinal epithelium, recent evidence suggests that there may be ways of manipulating the system to optimize the uptake of drug molecules. Dr. Igor D’Angelo is investigating the permeability of the intestinal epithelium lining the gut. Permeability is controlled by sites (intracellular tight junctions) that link these cells together – it is a complex, but poorly understood structure. Research indicates that Increased permeability of the lining is associated with severe allergies, autoimmune diseases like diabetes, tissue inflammation and cancer metastasis. It also is known that several types of bacteria produce toxins that increase permeability by opening up the tight junctions between these cells. Igor’s research is directed at understanding how these tight junctions are altered and how the mechanisms underlying those changes could be exploited to improve uptake of drugs in the treatment of disease.
Development of a genetic-based prediction model for cardiovascular disease and cancer risk assessment in neurofibromatosis type 1
Neurofibromatosis 1 (NF1) is a genetic disease associated with a variety of skin abnormalities and an increased risk of developing cardiovascular disease and cancer. About one third of people with NF1 die before age 45; usually from one of these complications. However, the risk of developing cardiovascular disease and cancer is not the same in all NF1 patients, with some people at higher risk of developing these complications. These differences are seen both between families with different mutations of the gene that causes NF1 and within families with the same mutation. Alessandro De Luca is exploring whether certain specific alterations of the NF1 gene and differences in other genes that interact with the NF1 gene are linked to an increased risk of cardiovascular disease and cancer. Alessandro is studying the frequency of particular NF1 mutations and variants of interacting genes in NF1 patients with and without cancer and cardiovascular disease. The ultimate aim of his research is to develop a panel of genetic markers that can be used to predict the risk of developing cardiovascular disease or cancer in patients with NF1.
Supporting Success: The Role of Mentorship in Increased Health Services Research Capacity
Research programs in Canada embrace mentorship as a way to increase research capacity, with experienced researchers mentoring more junior investigators. The three major research granting agencies in Canada (CIHR, SSHRC and NSERC) identify mentorship of new researchers as integral to research training. But few questions have been asked about how to make mentorship effective. For example, is an effective mentor someone who oversees career development, or provides guidance for a trainee? Dr. John Egan is evaluating how mentorship works in collaborations between university and community-based researchers. He is examining how mentors and their trainees experience mentorship, in a program jointly funded by the Canadian Institutes of Health Research and MSFHR. This research should identify what creates successful, productive mentoring, and lead to evidence-based practices and policies for effective mentorship