Research Pillar: Biomedical

Diabetes is a leading cause of death in Canada, affecting more than two million Canadians. Type 1 diabetes occurs when the pancreas fails to produce insulin, a hormone that is vital to transforming the sugars ingested in a meal to useable forms of energy. As a result, diabetic patients often depend on multiple daily injections of insulin to survive, but these injections do not prevent a series of long-term complications such as increased risk of heart disease, kidney disease and blindness. Type 1 diabetics can be treated by transplantation of islets—cell clusters from the pancreas containing insulin-producing cells—from non-diabetic donors. However, this option is severely limited by a shortage of donor islets. Therefore, there is interest in generating other cells that can also produce insulin. To be effective and safe, such cells must be capable of producing insulin in an amount that matches the quantity of sugar ingested. Like the insulin-producing islet cells, there are cells in the gut that are activated after a meal. These cells do not produce insulin, but another protein called glucose-dependent insulinotropic polypeptide (GIP). Recently, scientists were able to genetically modify these gut cells to produce insulin in addition to GIP. Building on this discovery, Irene Yu is working to develop methods to isolate and purify these cells and to determine how long these genetically modified cells can survive after transplantation. She is also testing whether these cells can effectively maintain normal blood glucose levels. If so, there will be an alternative to islets that can be used for transplantation, providing more type 1 diabetes patients with a longer-lasting treatment option.

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.

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.

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.

Although humans come into contact with pathogens (disease-causing microorganisms) regularly, these encounters only rarely result in infections. Most of the time, our innate immune response system quickly eradicates potentially harmful bacteria. Innate immunity is always available, rapidly turned on, and effective against a broad range of pathogens. However, the innate immune response can also lead to tissue damage and sepsis (bloodstream infection) if over-stimulated. For her PhD research, Jennifer Gardy fine-tuned PSORT-B, a software program she developed. The program examines the biological features of proteins in disease-causing bacteria to predict where they will most likely reside. As a Post Doctoral Fellow, Jennifer is creating a computer model of the genes and proteins that comprise the innate immune system and their interactions with each other. The model will enable her to predict the effect of removing a specific gene on the immune system as a whole. This research could reveal important insights about the functions of many of the genes involved in innate immunity, and lead to the development of novel therapeutic approaches to treat a broad range of bacterial infections and autoimmune disorders.

How brain cell activity alters blood flow in the brain is unclear, even though the phenomenon was first reported in 1890. Astrocytes are major support cells in the brain, that form enlarged, club-shaped endings called endfeet. These endfeet wrap around all blood vessels, giving them the opportunity to control blood vessel diameter. A recent discovery has shown that changes in calcium levels in the endfeet trigger dramatic constriction in blood vessels. Although nerve cells can initiate this process by signalling to the endfeet, prolonged nerve cell activity can also result in the blood vessels dilating to supply oxygen and other nutrients to the nerve cells. Dr. Grant Gordon is investigating how nerve cell activity counters the constriction caused by the astrocytes to increase the diameter of blood vessels. His goal is to determine whether signals from the nerve cells inhibit constriction, information which could lead to new drugs for people with impaired or damaged cerebral blood vessels, such as stroke patients.

Mast cells are part of the body’s immune system, residing in connective tissue and releasing compounds during allergic reaction or in response to injury or inflammation. They are found throughout the body, particularly at sites where pathogens can gain access, such as the gastrointestinal tract and the skin. As one of the first inflammatory cells to encounter an invading pathogen, they play a critical role in innate immunity and defense. Guntram Grassl is examining the role of mast cells in Salmonella infections to increase understanding of how these bacteria interact with host cells and how these interactions result in disease. He is determining how mast cells are activated in response to Salmonella and characterizing which factors mediate these effects. He is also studying how infections progress in the absence of mast cells. An increased understanding of how Salmonella causes disease may ultimately lead to the development of new ways to boost the innate immune response against bacterial infections and may lead to the development of new drugs that interfere with the way pathogens trigger disease.