Research Location: University of British Columbia - Point Grey

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.

Cerebellar ataxia is a rare neurological disorder that causes attacks of jerky, uncoordinated movements. Walking can become increasingly difficult, and eventually the use of a wheelchair is necessary. The name is derived from the word cerebellum, which refers to the part of the brain that controls balance and coordination. The condition has no cure and is irreversible. Treatment is available to alleviate symptoms, but not all patients respond to the drug of choice, acetazolamide. Genetic screening has revealed that one type of ataxia is caused by mutations in a particular gene. Interestingly, the same gene causes inherited forms of epilepsy and migraine headache. Simon Kaja’s studies are aimed at understanding the impact of ataxia on certain neuronal pathways in the brain. Nerve cells (neurons) connect one area of the brain to another, via pathways, to send and receive information. Simon is comparing mutated pathways with their healthy counterparts to determine how the ataxia gene causes disruptions or blockages in brain cell communication necessary for normal movement. Ultimately, the goal is to help develop new, more effective treatments.

Olfactory receptor neurons (ORNs) are the cells responsible for translating the odours in our external environment into the code that represents these smells in our brains. ORNs sense odours using receptors on their surface. These receptors bind the odour molecule by initiating a signalling process that results in information being transmitted to the appropriate part of the brain. Each ORN expresses only one type of receptor, and only a few out of thousands of other ORNs may express that receptor. This indicates that although all ORNs perform a similar function – sensing odours – each cell is unique. Since these cells are constantly exposed to the harsh external environment, they typically have a short life span. As a result, they are constantly replaced by new ORNS that are generated throughout life from undifferentiated cells. Thus, the olfactory system is the ideal model for understanding how an undifferentiated cell becomes a uniquely specialized neuron. Matt Larouche is seeking to define the time and place a particular ORN is produced since understanding these aspects may help explain what conditions are necessary for producing such a cell. This research will provide insight into how unique neurons are generated in the brain, and how to build specialized types of cells that can replace neurons lost due to injury. In the future, this information could be valuable for designing treatments for ailments that affect the nervous system, including strokes, paralysis and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer’s or Parkinson’s diseases.

One of the major challenges of neuroscience is the lack of regeneration of the mammalian central nervous system when it is injured. Extensive effort has been devoted to promote growth of regenerating axons (fibres that sent impulses from one neuron to another) across the lesion site. Since 55 per cent of spinal cord injuries are incomplete, in many cases a portion of axonal connections between brain neurons remain intact. These intact connections can be induced to form collateral branches, or sprouts, that cross the spinal cord midline and stimulate the other side, leading to some locomotion recovery. Finding ways to enhance this sprouting is a promising strategy to improve recovery in patients with incomplete spinal cord injuries. Ana Le Meur is using mathematical modelling to complement experiments to gain knowledge about the mechanisms regulating sprouting of neuronal connections. By generating a comprehensive model of collateral sprouting, this research will take an important step toward enhancing recovery after spinal cord injury.

Type 1 diabetes is a debilitating condition ultimately leading to severe, life-threatening complications that arise as a result of inadequate insulin secretion from the pancreas. Type 1 diabetes results from the destruction of insulin-producing cells by the affected person’s own immune system, requiring multiple daily insulin injections. While there has been much progress in the field of islet transplantation as a potential cure for type 1 diabetes, the limited availability of donor tissue and the requirement for lifelong immune suppression has led researchers to examine other potential methods for replacing insulin. Michael Riedel is investigating the potential to create cells capable of secreting insulin in response to a meal. With the goals of yielding insulin-producing cells, he is working with genes that encode the key proteins that are critical for the formation of pancreatic islets during development. Michael is also exploring another approach that involves looking for novel compounds to create insulin-producing cells and investigating their therapeutic potential. If successful, the creation of insulin-secreting cells could provide an additional source of replacement cells to combat type 1 diabetes.

Glutamate receptors are important for excitatory transmission between neurons and for basic neural function, and the NMDA-type glutamate receptor is widely expressed in the brain. Studies investigating the role of NMDA-type glutamate receptors have implicated their function in schizophrenia, pain, ischemia, addiction, synaptic plasticity and learning and memory. The majority of NMDA receptors cluster at synapses: interactions of certain regions of the receptor with proteins in the cell govern their transport and localization to the synapse. The number of NMDA receptors at synapses, and the composition of the subunits that make up the receptors, are important elements of the overall function of the nervous system. MSFHR funded Jacqueline Rose for her PhD work, where she used the microscopic worm C. elegans as a model to analyze how mutations in Presenilin genes affect learning and memory. Now, Jackie is researching the molecular mechanisms underlying the transport of NMDA-type glutamate receptors to synapses, and determining how this affects plasticity, thought to underlie memory and learning, at the cellular level. By developing specific mutations that will prevent certain proteins from interacting with particular NMDA-type glutamate receptor subunits, she hopes to shed further light on the receptor regions necessary for glutamate receptors to move to synapses during activity-dependent plasticity.