Depressive disorders are a leading global cause of disability. Although the incidence of depressive disorders is two-fold higher in women compared to men, the neurobiological basis for this disparity is unknown. Depressive disorders are often characterized by elevated blood levels of the glucocorticoid steroid hormone, cortisol. In both humans and rodents, females secrete greater levels of glucocorticoids than males in response to stress, which may at least partially explain the increased rates of affective disorders in women.
Dr. Nirupa Goel's research aims to elucidate the mechanisms behind the gender differences in stress responses. Previous studies suggest that deficits in serotonin neurotransmission may be a central cause for the increase in glucocorticoid secretion in depression. Most of these findings, however, come from research using male subjects. A critical first step for Dr. Goel is to identify how serotonin contributes to the gender difference in stress responses. The results of her preliminary studies indicate that blocking the serotonin 1A receptor reduces the glucocorticoid response to stress and that this effect is larger in male than in female rats. In brain tissue from the same animals, there were marked gender differences in stress-induced neuronal activation of the serotonin-producing dorsal raphe nucleus and of forebrain regions that regulate glucocorticoid release.
Based on the strength of her initial findings, Dr. Goel will further examine how stress, gender and serotonin intersect in the brain. To do this, she will measure biochemical markers of serotonin function in male and female rats under basal conditions and in response to repeated stress exposure. She will use serotonin receptor blockers to determine which receptors are involved in the gender differences in stress adaptation. Overall, these studies will elucidate the mechanisms by which serotonin mediates sex differences in stress responses. The findings have realistic clinical implications for discovering individual and sex-based differences in the development and potential treatments of affective disorders.
Ovarian cancer is the most lethal cancer of the female reproductive system and the fifth leading cause of cancer-related death in Canadian women. Ovarian cancer is not one disease, but rather comprises several tumour types that likely develop through unique mechanisms from different cell types. Previous research suggests two types of ovarian cancer — clear cell carcinoma (CCC) and endometrioid carcinoma (EC) — may develop from ovarian endometriosis, a condition associated with increased inflammation. Dr. Alicia Tone is investigating how endometriosis-associated inflammation can influence the development of CCC and EC by looking at the specific role that the ARID1A gene plays in inflammation. ARID1A has been shown to increase the activity of the glucocorticoid receptor, which plays a crucial role in reducing the duration and intensity of an inflammatory response. In addition, the ARID1A gene was recently found to be mutated in both CCC/EC, and the mutated gene is associated with endometriosis lesions. Dr. Tone intends to 1) identify which specific inflammatory genes are altered in CCC/EC cells and associated endometriosis; 2) compare the response of cells obtained from endometriosis and CCC specimens with and without mutations in the ARID1A gene; and 3) determine the mechanism by which ARID1A regulates the response to inflammatory mediators. This study will help our understanding of how endometriosis may develop into ovarian cancer (CCC and EC); more importantly, pointing to the development of new preventive strategies. Research aimed at understanding what is involved in the early stages of development of these different cancers may reduce the number of deaths associated with ovarian cancer.
More than 50 million people worldwide suffer from epilepsy. Approximately 90 percent of those treated with current drugs experience significant side effects, and around 30 percent do not respond to current medical treatments at all. Therefore, significantly better treatments are required to improve the quality of life for epilepsy sufferers in Canada and worldwide. To achieve this, a far greater understanding of how the brain works both normally and during seizures is necessary.
Epilepsy is a difficult disorder to study in humans; however, in the 1980s, a strain of rats that naturally suffer from a type of seizure very similar to the human condition and involving the same brain regions was identified. These rats are extremely useful in helping us understand the causes of epilepsy in humans and test new drugs being developed to treat epilepsy. Two years ago, Dr. Stuart Cain’s research characterized a newly discovered genetic mutation in the epileptic rat strain responsible for a large portion of seizures. Epileptic seizures can be caused by changes in the way certain brain nerve cell proteins, known as "calcium channels," conduct electricity — the mutation characterized by Dr. Cain alters the way in which a specific type of calcium channel conducts electrical signaling. This was significant as these particular calcium channels are able to generate patterns of electrical pulses, known as “firing patterns,” predicted to contribute to epileptic seizures.
Dr. Cain’s research project aims to determine how the calcium channel mutation alters communication between nerve cells and affects different firing patterns. His laboratory is the only site in North America currently studying the epileptic rat strain. Understanding what causes the firing properties of epileptic nerves to change during seizures should allow the design of new drug treatments with the ability to block these changes directly, and to also reduce side effects compared to many of the broad-target drugs currently used clinically.
Blood transfusion is a critically important medical procedure used to treat blood loss due to trauma or during surgery; it is also used in the treatment of chronic blood disorders such as thalassemia, sickle-cell disease and other forms of anemia. Due to the presence of blood antigens, however, careful blood typing is necessary to avoid the adverse and sometimes fatal reactions that may result from a mismatched blood type during transfusion. The A and B blood antigens are considered the most clinically important blood antigens. These antigens consist of carbohydrate (sugar) molecules attached to the surface of blood cells. People with type O blood lack the A and B antigens on their red blood cells and thus are often considered “”universal donors”” (not accounting for minor antigens), yet units of type O blood are frequently in short supply due to high demand. The use of enzymes to remove A and B antigens is a potential means of generating universal blood donor cells from blood types other than O. Dr. David Kwan’s research aims to investigate methods for the enzymatic removal of blood antigens from blood cells. Although enzymes that remove the A or B antigens to convert red blood cells have been discovered, they have low efficacy. Recently a new enzyme called EABase was discovered, which can efficiently remove the B antigen but only slowly removes the A antigen from red blood cells. The primary focus of Dr. Kwan’s work will be to engineer the EABase enzyme using “”directed evolution”” techniques to improve the efficiency of EABase in removing blood antigens so that it may be a more efficient catalyst for the conversion of A-, B- and AB-type red blood cells into “”universal blood cells.”” A secondary focus, in collaboration with the Centre for Blood Research, will test the use of polymer additives to enhance the rate of enzyme action. Over 15 million units (approximately 450 ml per unit) are collected for preparation of blood products in Canada and the United States per year. The ability to generate universal blood donor cells would be a breakthrough development, allowing transfusion without the need to find a positive match and tremendously improving the supply of blood while increasing the safety of blood transfusions.
Complex surgical procedures on the face, such as jaw reconstruction, frequently result in problematic scars that may be aesthetically upsetting for the patient or can interfere with chewing or swallowing. An accurate facial computer model of a patient’s face could allow surgeons to test different surgical incision pattern designs before surgery to determine which design is likely to result in the best outcome. A computer model of a patient’s face must take into account the complex properties of facial skin, such as the variability of stretch depending on direction. This requires experimental data from tests on a real human face; however, there is little data available at present about the stiffness of facial skin and soft tissues. The goal of Dr. Cormac Flynn’s research is to determine how the complex properties of facial skin affect our chewing and swallowing actions and how facial scars interfere with these functions. He aims to develop a computer model of the face with the most accurate representation of facial skin possible. To do this, he will use a biomedical device to determine the stiffness and thickness of skin and soft tissue below the skin surface of volunteers. His second task will be to use a small robotic device to apply small forces to a volunteer’s face and measure how much the skin surface deforms. The force will be applied to a number of points on the face in succession to provide a rich set of data that will be used to develop the skin model. Dr. Flynn will determine appropriate computer models to represent the skin and underlying soft tissue and apply his data from the first two experiments to set the parameters. Finally, he will merge the face model with an existing computer model of the jaw and tongue developed at UBC. The ability of the resulting model to simulate chewing and swallowing will be compared with existing computer models. This research will provide crucial knowledge about how facial skin and the underlying soft tissues influence chewing and swallowing, and will be used in the development of a computer model that surgeons can use to improve both reconstructive surgery outcomes and quality of life for patients.
Type 1 diabetes, also known as juvenile diabetes, is an autoimmune disease that usually presents in children and young adults. In patients with Type 1 diabetes, the body attacks itself, thus destroying insulin-producing cells in the pancreas that regulate blood sugar (glucose). A diagnosis of Type 1 diabetes currently translates to a lifetime burden of insulin injections and a risk of multiple complications for children in Canada. T-cells are white blood cells and play a key role in the immune system to control infection. In healthy individuals, a type of T-cell, called Th17, provides a strong defense by guiding the immune system to attack bacteria and virus-infected targets within our bodies. A recent discovery of elevated numbers of Th17 cells in children newly diagnosed with Type 1 diabetes suggests that these cells may play a key role in the early development of this disease in young patients. Interestingly, Th17 cells have been associated with other autoimmune diseases, such as Crohn’s disease and multiple sclerosis. Dr. Ashish Marwaha is working to identify novel treatments for Type 1 diabetes by understanding the function of Th17 cells in the course of a child developing Type 1 diabetes. To understand if there is a specific genetic mutation that can predict which children will have high levels of Th17 cells and therefore at risk of developing Type 1 diabetes, he will be analyzing stored blood samples from British Columbian children with this disease. The findings from this study will determine the extent to which Th17 cells are harmful in Type 1 diabetes and may open the door to new treatments for childhood diabetes that target Th17 cells.
Within each individual cell, different proteins are localized to specific and necessary locations. There are many different ways these proteins are directed to where they need to go. One method for influencing protein localization is palmitoylation, which is the addition of a lipid molecule, specifically palmitate, to the protein. Protein localization is especially important in neurons, where synaptic proteins need to be carefully organized and localized to the pre- and post-synaptic regions of the neuron in order to accurately convey messages from one neuron to another. In Huntington's disease, which is characterized by neuronal death and subsequent severe motor and cognitive disturbances, it appears that synaptic proteins are mis-localized outside of the synapse, which causes synaptic dysfunction prior to cell death and symptom onset. Preventing this early synaptic dysfunction is believed to be a viable means of preventing or significantly delaying cell death and Huntington’s disease symptoms. Previous work has suggested that the level of palmitoylation is decreased in Huntington’s disease and that this may contribute to early synaptic protein dysfunction. Dr. Matthew Parsons is working to determine how the palmitoylation of specific synaptic proteins regulates their localization within the synapse and how this relates to the synaptic dysfunction observed in Huntington’s disease. Specifically, he is using different techniques to compare the properties of synaptic communication, synaptic protein localization and neuronal vulnerability to cell death in mice that have Huntington’s disease and mice with reduced protein palmitoylation. He will also use neuronal cultures from wild-type animals to investigate the effects of experimentally manipulated protein palmitoylation. Should the synaptic dysfunction due to decreased palmitoylation resemble the synaptic dysfunction in Huntington’s disease, he will also attempt to rescue the early Huntington’s disease phenotype by overexpression of a protein known to promote palmitoylation. These studies will help determine whether the regulation of synaptic protein palmitoylation may be a viable target for the treatment of Huntington’s disease.
Sufficient blood flow to the brain is critical for normal brain function. In response to increased brain activity, a local increase in blood flow to the active area is required to supply extra oxygen and glucose. This increase in blood flow is controlled by signaling molecules, which are released by neurons and astrocytes and can regulate blood vessel diameter. Dr. Clare Howarth will investigate how brain blood flow is controlled in response to increases in brain activity and how this is impaired in disease. In particular, she will be studying the role that astrocytes, a type of brain cell, play in the regulation of brain blood flow. One of the signaling molecules released by astrocytes, prostaglandin E2, can result in blood vessel dilation. Dr. Howarth’s hypothesis is that following a stroke, astrocytes have a decreased ability to produce prostaglandin E2, and this contributes to the long-lasting failure of blood vessels to dilate, leading to increasing neuronal damage. Using multi-photon imaging techniques, she will observe what happens to blood flow in the brain when astrocytes are stimulated with pharmaceutical or light-activated agents under conditions where the production of these signaling molecules is compromised. She will also investigate whether pharmaceutical therapies are able to reverse the effect, allowing blood vessels to dilate and help recover brain function after a stroke. This work will advance our understanding of how brain blood flow is regulated in response to neural activity. This knowledge is essential to understanding normal brain function, functional imaging techniques, and what occurs when the brain energy supply is cut off in disorders such as a stroke.
Circulating T-cells are the key players in our adaptive immune system and are particularly important for recognizing and killing cells that are infected with viruses or carry cancer-causing mutations. T-cells have the ability to potentially recognize vast numbers of different infectious agents and cancer- or tumour-associated mutations. The T-cell receptor, on the surface of the T-cell, is responsible for this task, and the variation required for recognition is generated mainly by shuffling the large number of short DNA segments that comprise T-cell receptor genes. Although the central importance of the T-cell receptor in adaptive immunity is well established, the actual number and diversity of T-cells that exist in an individual (i.e. the T-cell repertoire), how this changes in response to immune challenge, and how it varies from one individual to the next, remains a mystery. Dr. Rob Holt’s lab is using the latest DNA sequencing technologies to directly sequence T-cell receptor genes in order to examine the T-cell repertoire in a given blood sample. Using this approach, the lab has identified populations of unique T-cell repertoires in bone marrow stem cell transplant patients and in colorectal cancer patients. Dr. Kristoffer Palma’s research project is to take this approach one step further by developing a novel, high-throughput screen for the molecular patterns (antigens) recognized by donor T-cells and to find out how these are related to transplant success in bone marrow transplants. The second application of his research is to determine if there are T-cell receptor commonalities in patients with colorectal cancer tumours, how T-cell receptor commonalities relate to disease prognosis, and what tumour-associated antigens may be recognized by T-cells in patients with high survival rates. In the case of bone marrow transplants, Palma anticipates that his research will lead towards the earlier diagnosis and intervention in graft versus host disease, which is the most immediate and life-threatening complication of bone marrow transplant, affecting 30 to 80 per cent of patients. With regard to colorectal cancer, Palma hopes his research will contribute to the creation of a high-resolution diagnostic screening test to identify early stage cancer that would be undetectable with current assays and aid in the eventual development of cancer-specific vaccines.
Blood transfusion has a vital role in modern medicine. Not only is it required in surgery, or for the treatment of acute trauma, but patients with disorders such as thalassemia major and sickle cell anemia require chronic transfusion therapy on an ongoing basis. In chronic transfusion therapy, matching of minor antigens besides the major ABO and RhD antigens is essential; unintentional mismatching of red blood cells remains one of the most common causes of serious and fatal adverse reactions following transfusion. Creation of universal donor red blood cells has the potential to significantly decrease such incidents. Presently, there is no method available for the generation of antigen- red blood cells, in part because of the complexity of proteins on the surface of red blood cells. Previous attempts to create universal donor red blood cells include enzymatic cleavage of terminal immunodominant sugars and the covalent attachment of hydrophilic polyethylene glycol (PEG) polymers to surface proteins on red blood cells to camouflage the antigens. Enzymatic cleavage remains expensive and PEG-grafted red blood cells demonstrated shortened circulation in animal models. Dr. Rafi Chapanian’s research aims to use a novel cell-surface engineering method that combines grafting of highly biocompatible polyglycerol polymers and enhanced enzymatic cleavage of AB antigens to create universal donor red blood cells. He will develop a new powerful class of enzymes that can simultaneously remove group A and B antigens. He will use neutral additive polymers to enhance the efficiency of enzymatic cleavage and will investigate polymer grafting to make the process cost effective. Dr. Chapanian will synthesize linear, branched, and umbrella-like polyglycerol-based polymeric structures and graft them to the primary amines of proteins on the surface of red blood cells. These polyglycerol polymers are highly biocompatible, non-immunogenic and are expected to be superior to PEG polymers. Modified red blood cells will be characterized using standard in vitro testing methods and ultimately will be injected in mice to investigate their circulation. This research holds great promise for the cost-effective generation of antigen- red blood cells and has the potential to significantly improve the blood supply and enhance transfusion safety.
