Research Location: University of British Columbia - Point Grey

Stem cells are defined by their unique capabilities to either replicate (self-renew) or differentiate into more specialized cell types such as nerve cells (neurons), immune cells and skin cells. If health researchers could controllably direct stem cells to differentiate into particular cell types, stem cells could potentially be used as clinical therapeutics for a diverse range of diseases, including neurodegenerative diseases, autoimmune disorders, heart and liver disease, and cancer. Presently, the control of stem cell differentiation is hampered because researchers lack the necessary knowledge and tools for studying the molecular pathways that guide stem cell differentiation into specific cell types. Anupam Singhal’s research seeks to harness recent advances in micron-sized fluid-handling devices and nanotechnology in order to quantitatively study stem cells at the single cell level. In particular, he will propose a general platform for performing rapid and high-throughput quantification of multiple proteins in single stem cells. This strategy should help to identify proteins (e.g. transcription factors for gene expression, secreted proteins) that influence the stem cell fate decision. This information will then be used to construct model molecular pathways that guide stem cell differentiation, a critical milestone that must be reached before stem cells will find widespread clinical applications.

Currently 30 million Americans suffer from some form of clinically recognized memory disorder. During the last 25 years, basic neurobiological research has begun to identify the underlying molecular mechanisms for memory formation. One of the key players discovered to be involved in the formation of protein synthesis dependent long-term memory (LTM) is the transcription factor cAMP response element binding protein (CREB). CREB has been shown to be a necessary protein for the formation of LTM in diverse species including sea hares, fruit flies, mice and humans. Tiffany Timbers is exploring whether CREB is also essential for the long-term habituation observed in Caenorhabditis elegans (a tiny nematode), which can become “used to” repeated stimulation such as tapping on the Petri dish where it lives. Tiffany will determine whether CREB activity (resulting in the transcription of cAMP responsive genes) occurs in the neurons that generate the plasticity responsible for LTM. By investigating the involvement of CREB in the biological pathway underlying the memory of habituation in C. elegans, this research could contribute to the development of new gene targets, drug screens and preclinical data to suggest drug classes capable of helping those affected by memory cognition defects.

Potassium channels play an essential role in controlling the activation of neurons (nerve cells), myocytes (muscle cells) and the endocrine system. In particular, their proper function and behaviour in the heart is of the utmost importance in maintaining proper cardiac function. Acidosis (a lowering of blood pH) is caused by cardiac ischemia, or an insufficient blood supply. It has been shown that acidic pH levels alter ion channels, possibly through a structural change in the pore region. This condition is linked to cardiac abnormalities such as arrhythmias and cardiac arrest. Moninder Vaid is focusing on acidic alteration of cardiac ion channel function to determine how pH modulates ion channel structure. He using fluorescent techniques to further examine how ion channels work in mammals. Ultimately, this research will provide insight into the effects of cardiac ischemia.

Messages are relayed through the nervous system by release of neurotransmitters from an axon of one neuron, which travel across the synaptic cleft and bind to receptors on a dendrite of the next neuron. The axon terminal, synaptic cleft and dendrite are collectively called the synapse. The formation of synapses—known as synaptogenesis—is the most central process in the development and maintenance of the nervous system. New synapses are formed during learning and memory and the maintenance of synapses can be altered in disease and drug-induced states. Katherine Walzak’s research is focusing on the process by which synapses form and change with experience. Specifically, she is exploring how neurotransmitter receptors on postsynaptic dendrites are aligned with neurotransmitter release sites on presynaptic axons, and how cell adhesion molecules influence synapse differentiation and localization. By understanding the mechanisms by which synapses forms and are maintained, this research may lead to further insights into disease that may involve the alteration of synaptogenesis, such as Alzheimer’s, schizophrenia and autism spectrum disorders.

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.