Research Location: University of British Columbia - Vancouver Campus

Aging and developmental change represent body wide changes in genes. Because many genes change as people age, the relationships between genes also often change, a phenomenon called differential coexpression (of RNA levels). Studying differential coexpression has uncovered changes that cause disease. However, knowledge gaps remain with respect to relationships between disease and aging in neurological diseases, for example. Many diseases have a specific age of onset, schizophrenia for example, typically strikes in early adulthood. This suggests that in multi-gene disorders, where interactions between genes play a role, rewiring may occur between susceptibility genes at the age of disease onset. Dr. Gillis’s current research project builds on his earlier work which showed that aging is associated with numerous changes in coexpression, and that genes known to be associated with specific diseases change their relationships with age in healthy individuals. His current project involves studying how the relationships between candidate genes – differential coexpression – in schizophrenia and Alzheimer’s Disease, change as a function of age. By understanding how networks of gene interactions might be rewired in diseases, we can identify candidate genes that would be missed otherwise, and beneficially influence the design of treatments and diagnostics.

Understanding the role of the microbiota in the development and progression of diseases has received a great deal of attention in recent years. The microbiota is defined as the group of microorganisms, such as bacteria, which normally inhabit the human body. These microorganisms, also known as microflora, are composed of a variety of species of bacteria, each having a different function, and there are some bacteria whose functions remain unknown. Several studies have shown that patients with inflammatory bowel diseases, such as Crohn’s Disease, have a microbiota composition that is different from healthy individuals, suggesting that certain species of bacteria might be important in causing some common gut inflammatory disorders. Dr. Navkiran Gill is investigating how the human immune system regulates the microbiota and how our microbiota may direct our immune responses to various pathogens. Specifically, she is doing a series of experiments involving antibiotic use in specially bred mice infected with Salmonella. The results will provide important information regarding the effect of antibiotics on the microflora, and allow her to correlate changes in our microflora to changes in our ability to mount an immune response against a pathogen such as Salmonella. The results of Dr. Gill’s research will provide information that may be used to design new therapeutics that take into consideration the important role of our microflora.

While we know that Type 1 diabetes is caused by the destruction of insulin-secreting beta-cells in the pancreatic islets, the processes that regulate beta-cell death remain unclear. This has hindered the development of strategies to halt or prevent the development of diabetes. One possible new treatment, islet transplantation, was initially heralded as a promising therapy for Type 1 diabetes because it removed the need of daily insulin injections. However, the transplanted beta-cells were found to gradually die, which resulted in transplant recipients having to resume the use of insulin injections. In order for islet transplantation to be effective, new approaches to promote islet survival are required. In earlier work, Dr. Gareth Lim’s colleagues identified insulin as a critical pro-survival factor for beta-cells. Their findings suggest that secreted insulin from beta-cells may promote self-survival. However, the mechanisms that lead to the beneficial effects of insulin need to be clarified. Consequently, Gareth Lim is currently investigating the mechanisms by which insulin acts on the beta- cell. Specifically, he is doing a series of experiments to show that the protein Raf-1 kinase, which is activated by insulin and has been shown to have an important role in regulating cell death, is essential for beta-cell survival. The results of his studies will improve our understanding of the mechanisms of beta-cell death. They may also lead to novel therapeutic strategies for preventing beta-cell destruction in Type 1 diabetics and their at-risk relatives. Furthermore, an understanding of the pathways involved in beta-cell survival may also lead to new methods to increase the survival of beta-cells after islet transplantation, thereby increasing the effectiveness of this treatment.

In Type 1 diabetes the body’s immune system attacks key cells of the pancreas known as beta-cells. The loss of these cells results in a loss of the protein hormone insulin which is secreted by the beta-cells in response to high blood sugar levels. Recently, advances in the field of pancreatic islet cell transplantation have shown that the replacement of beta-cells represents a possible cure for diabetes. Unfortunately, the poor availability of donor organs to provide the transplantation cell source greatly limits the use of this treatment. One promising possible source of new beta-cells for transplantation is human embryonic stem cells (hESCs,) and a number of researchers have shown that these cells can form pancreatic tissue including beta-cells. Blair Gage is currently exploring how proteins known as transcription factors (TFs), control the formation of beta-cells from hESCs. Specifically, he is investigating whether adding TFs, which help in the formation of beta-cells, and removing the TFs, which block the formation of beta-cells, will help in understanding how to control hESC growth and development. The results of Mr. Gage’s research will enhance ongoing work with industry and the Canadian Stem Cell Network that is focused on stimulating hESCs to form beta-cells for transplantation. The ultimate goals is to apply this technology to the treatment of patients with diabetes in a similar way to that of islet tissue transplantation, using a theoretically limitless supply of beta-cells.

Alzheimer’s disease (AD) is the most common neurodegenerative disease in humans, affecting millions of people worldwide. Currently, there is no cure for AD or treatment that can mitigate the disease process. However, recent research has revealed beta-site amyloid precursor cleaving enzyme 1 (BACE1), as a promising therapeutic target for AD. BACE1 is the protease that cuts Amyloid Precursor Protein (APP) at the beta-site. This cleavage of APP triggers a second cleavage, which releases the Amyloid-beta fragment. Accumulation of Amyloid-beta is believed to initiate the catastrophic cascade of events that lead to the onset of AD. Animal data suggest that BACE1 inhibition prevents Amyloid-beta formation and may be well tolerated, and therefore, BACE1 is considered one of the most promising drug targets for preventing and mitigating AD. However, recent work has revealed that APP is not the only substrate of BACE1. Consequently, drug-targeting strategies will modulate processing of both known and unknown substrates, any one of which may lead to undesirable or deleterious side effects. Therefore, the identification of all BACE1 substrates is necessary to predict and understand side effects of BACE1 inhibitors. Pitter Huesgen is working to identify new substrates and pathways modified by BCAE1 and the related enzyme, BACE2. His results will provide essential information on the complex physiological functions of BACE1 and BACE2 and their roles in the pathogenesis of AD, and help to predict side effects of BACE1 inhibitors, which will ultimately decide if BACE1 inhibition is a viable treatment strategy for AD.

Responding and adapting to environmental changes is crucial to the survival of all living organisms, including cells. Cells use signaling cascades to detect stimuli in their environment and respond by altering the expression and turnover of specific genes and proteins. Since many signaling events are regulated by the addition of a phosphate to serine, threonine, or tyrosine residues on proteins within these cascades, identifying and characterizing these modifications is crucial to understanding how signalling pathways function. Until very recently, studying protein phosphorylation has been a slow and laborious process, as existing techniques limited researchers to studying only a few phosphsphorylation sites in isolation. However, the recent emergence of highly sensitive techniques in liquid chromatography-tandem mass spectrometry (LC-MS/MS), has enabled scientists to analyze thousands of phosphorylated proteins simultaneously. Lindsay Roger’s research utilizes LC-MS/MS to analyze thousands of protein phosphorylation events simultaneously in cells infected by Salmonella. Salmonella is an intracellular bacterial pathogen which, in humans, causes gastroenteritis and typhoid fever and is one of the most common and widely distributed food borne illnesses. During infection, Salmonella use a needle like complex to transport bacterial proteins, termed effectors, into host cells where they mimic host proteins and influence signalling. Currently, little is known about the host targets of the majority of Salmonella effectors and how they cause disease. Using these LC-MS/MS experiments, Ms. Rogers’s research is identifying a myriad of novel host targets of these proteins. It is expected that this research will provide a considerable leap in our understanding of how Salmonella infects its host.

In recent years, there has been a marked improvement in the clinical classification of individual cancer sub-types based on their detailed genetic and pathophysiological analysis. While this has had a tremendous impact on determining patient diagnosis, current treatments used to block the spread of tumour cells have largely been unsuccessful, and metastasis (the spread of tumour cells from a primary tumour to secondary sites), remains responsible for 90 percent of cancer deaths. Notably, the number of cancer cells that have the capacity to reach the bloodstream correlates with primary tumour size, and when diagnosed with cancer, patients can expect to have between 100,000 and more than one million circulating tumour cells in their blood. This apparent inefficiency of tumour cells to get out of the bloodstream and proliferate may be an important avenue for therapy, as maintaining and/or enhancing this inefficiency could be a key step in blocking the spread of cancer. Recently, Spencer Freeman has been investigating this possibility. His research has provided general information on how tumour cells adhere to and migrate out of the blood vasculature, and he has identified Rap1 and integrin as critical regulators of tumour cell adhesion. Moreover, Mr. Freeman and colleagues have been able to block this pathway using antibodies and genetic approaches, which has reduced the ability of tumour cells to adhere to and migrate out of the vasculature in vitro as well as in animal models. In his current research project, Mr. Freeman is investigating the underlying mechanism, in particular the signalling events, which mediate communication between tumour cells, circulating blood leukocytes and vascular endothelial cells. The results of his research will improve our understanding of the genetic axis and physical steps that tumour cells use in order to first colonize distant sites. In turn, this knowledge may lead to improved cancer treatments against metastatic disease.

Just how neurons form appropriate connections to develop into functional neural networks remains an important unanswered question in neuroscience. During early brain development, sensory neurons form and refine synaptic connections to respond to and encode information about a specific set of inputs, which is termed their ‘receptive field’ (RF). While previous experiments have investigated the development of numerous RF properties, most studies have focused on individual neurons, or a small number of neurons distributed sparsely in a brain region. In contrast, the changes which are thought to underlie learning, such as synaptic plasticity, are intimately dependent on how the firing patterns of different neurons interact. In his research, Kaspar Podgorski is using two-photon imaging of calcium sensitive-dyes and a mathematical model of how neuron firing affects calcium levels to observe the RF responses of hundreds of interacting neurons in awake Xenopus tadpoles. These data will provide information about how networks of neurons work in synchrony to encode information about the world. Mr. Podgorski images network activity before, during and after visual training that improves the discrimination abilities of the neural network. The aim of his research is to form a mechanistic understanding of how the firing patterns of individual neurons and the interactions between them change in order to improve whole network function. By studying how local properties come together to make large neural circuits function more effectively in the intact, awake brain, we will gain a better understanding of normal brain circuit function and potentially determine the origins of developmental brain disorders such as schizophrenia, epilepsy and autism, which may be caused by abnormal circuit development.

Neurodegenerative diseases associated with aging, such as Alzheimer's disease (AD,) effect millions of people annually. The development of AD may be related to gonadal hormones present in adulthood. Interestingly, women have an increased risk for developing AD compared to men. Additionally, the disease progresses more rapidly in women and the onset of AD is generally earlier in women than in men. The ovarian hormone estrogen has been implicated as a possible therapeutic agent for improving cognition in postmenopausal women and AD patients, and epidemiologic evidence indicates that hormone replacement therapy (HRT,) reduces the incidence of and/or delays the onset of AD in women. However, there is evidence to suggest that the beneficial effects of estrogen on cognitive impairment associated with aging in women may depend upon the type of estrogen (e.g. estrone versus estradiol), taken. Interestingly, estrogens are known to exert significant structural and functional effects on the hippocampus, a brain region which retains the ability to produce new neurons throughout adulthood in all mammalian species studied, including humans, and is known to mediate some forms of learning and memory. Importantly, previous research has shown that the increased survival of newly produced neurons in the hippocampus of adult rodents are related to better hippocampus-dependent learning and memory. Cindy Barha is researching the effects of different types of estrogen on cognition and the production of new neurons in the hippocampus of young and older female rodents. The results of these experiments will have important implications for determining which alternative forms of estrogen to incorporate into HRT in the future. Ultimately, the results from these and other studies may lead to the development of new therapeutics that halt or slow the progression of neuronal loss in age-related neurodegenerative disorders.