Research Location: University of British Columbia - Point Grey

It is known that neurodevelopmental disorders such as Fragile-X Syndrome and autism have a strong genetic basis, yet the genes involved have not been clearly identified. Both disorders exhibit patterns indicative of abnormal or halted synaptic development (formation of the junction between neurons). Research indicates that these synaptic abnormalities may be the underlying neurological cause of these disorders. Genetic analyses of individuals with Fragile-x and autism revealed genes, and their proteins, thought to be involved in synapse formation and maintenance but the exact neurological mechanisms that lead to these diseases remain unknown. Rochelle Bruneau aims to clarify the role of the specific proteins involved in synapse development, testing for their implication in Fragile-X Syndrome and autism. She will study proteins involved in both the formation and function of synapses and hopes to examine potential therapeutic proteins for reducing the severity or preventing the onset of symptoms of neurodevelopmental disorders.

A technology that shows great promise in treating human disease is the use of viruses as vectors (or carriers) to insert and replicate new genetic material into the genome of a diseased cell. Parvoviruses are suitable candidates for use as vectors, including the parvovirus known as MVM (minute virus of mice). These viruses have been successfully tested in many preclinical models of human diseases, including cancer. As part of its replication cycle, the genome of MVM must enter the nucleus of its host cell. How MVM accomplishes this is unknown, but studies suggest that the way it breaches the nuclear membrane is unlike that of any other known virus. Sarah Cohen is using electron microscopy, combined with biochemical and genetic approaches, to investigate the mechanisms employed by MVM to enter the nucleus of a host cell. Gaining a more developed understanding of these entry mechanisms will aid in the development of MVM as a therapeutic vector, helping to bring MVM-based vectors into clinical trials. A successful vector for gene therapy could ultimately deliver healthy genes to patients for the treatment of a wide variety of genetic diseases.

Chemokines are small proteins that direct the migration of white blood cells (including T cells) in the body. This process is very important in mounting an immune response against invading pathogens. Chemokine function is known to be implicated in autoimmune diseases such as multiple sclerosis and graft versus host disease, and has recently been linked to the ability of cancer to spread from one part of the body to others. Jennifer Cox is investigating the ability of a family of proteases to process and alter chemokine activity. Focusing on a group known as matrix metalloproteinases, she has uncovered that one of these proteases cleaves specific chemokines, altering their ability to induce the migration of T cells. Now, she hopes to use mouse models to prove that this interaction is relevant in the body. These studies will result in a better understanding of immune regulation at a molecular level and could have implications for the prevention of cancer spread and the treatment of autoimmune diseases.

Mounting evidence suggests that many common neurological and psychiatric disorders, such as schizophrenia, autism, and epilepsy, originate from abnormal brain circuit formation and neuron (nerve cell) growth during early development. An increasing number of studies show that in addition to genes, conditions in our surroundings can influence neuron development during early life and in later years. One important contributor to abnormal neuron growth may be altered levels of glutamate (the primary neurotransmitter that nerve cells use to send signals across synapses) and its neurotransmitting capabilities – called glutamatergic synaptic transmission. For example, a reduced glutamatergic transmission has been associated with schizophrenia and an increased level with neonatal seizures. Derek Dunfield is investigating how neurons connect with each other and how activity influences those connections during development. Specifically he is measuring the influence of glutamatergic transmission on dynamic brain circuit growth. Derek is examining real-time imaging of neurons during development using a relatively new imaging technique called two-photon microscopy and a labeling technique called single-cell electroporation. This allows him to label single neurons with different colours and watch how they interact together as they grow. Derek hopes this research will lead to better treatment and diagnosis for disabling brain disorders.

Chemokines are small proteins that direct the migration of immune cells into and within the body’s immune system. These include B cells that become activated and mediate an immune response to infectious agents (antigens) that cause disease. Dr. Michael Gold’s laboratory is interested in understanding the function of the protein Rap1, a GTPase that is activated by binding to the nucleotide GTP. Dr. Gold’s lab has shown that Rap activation is involved in B cell migration towards certain chemokines. More recently, their research has indicated that Rap regulates the activation of Pyk2, a protein known to be required for B cell migration. As a trainee in Dr. Gold’s lab, Caylib Durand is studying how chemokine-induced signaling causes B lymphocytes and other immune cells to migrate, and how chemokine-mediated signaling activates Rap1 and Pyk2. His goal is to identify key signaling pathways that coordinate the events required for cell migration. Ultimately, Caylib’s work may indicate that Rap and Pyk2 might be good targets for drugs to regulate inflammation and immune responses.

A significant breakthrough in diabetes research occurred in 2000, when an Edmonton research group developed a protocol for transplanting insulin-producing cells from human donors into patients with type 1 (insulin-dependent) diabetes. More than 100 successful islet transplantations have been performed worldwide, bringing realistic hope for a cure to diabetes. Since two donors on average are required to acquire sufficient islets to treat one patient, a shortage of donor islets remains a significant obstacle for widespread use of transplantation. There is a great demand for alternative sources of these cells, such as cells derived from adult stem cells produced in the laboratory. Ideally, cells would be taken from a patient. From these, the appropriate stem cells would be isolated then cultivated to produce a supply of islet cells for transplantation back into the patient. Before this can be achieved, however, researchers must optimize techniques for increasing the numbers of pancreatic islet cells that can be produced in this fashion. Corinne Hoesli’s research focuses on duct cells, which are believed to be the precursors of insulin-producing islet cells. She is working both to determine the best ways to grow these cells in-vitro and how to translate these protocols to support larger scale production. As process optimization and scale-up are typical engineering issues, she hopes that applying engineering approaches to this field of health research will help overcome the bottleneck of tissue shortage for islet transplantations.

The selective passage of ions through channels in cellular membranes provides the molecular basis for many cellular processes. This includes control of the initial phase of depolarizations that lead to contraction of the heart. Upon initiation of contraction, sodium ion channels open briefly, and then are inactivated by a portion of the protein that “”plugs”” the channel pore, preventing further ion passage. Recently, a much slower form of channel inactivation has been discovered, which researchers believe is controlled by a separate, co-existing mechanism. One theory suggests that slow inactivation occurs when the protein components responsible for the selective passage of sodium ions constrict, causing complete occlusion of the pore during periods of prolonged or rapid openings. Certain drug classes work by blocking sodium channels, such as local anesthetics and a sub-class of anti-arrhythmic drugs, both of which can be used to treat an irregular heartbeat. There is limited understanding of how these drugs affect, or are affected by, the slow inactivation process.