Mechanisms of topical calcipotriol mediated tolerance induction

Autoimmune diseases such as type 1 diabetes, lupus, and multiple sclerosis are a serious health issue in North America, affecting more than 22 million people in the US alone. Unfortunately, current treatment options for individuals suffering from autoimmunity are limited, and patients are often faced with the prospect of life-long drug regimens designed to suppress their immune systems. While effectively managing autoimmune diseases, these drugs can also hamper the body’s ability to defend itself against infection and cancer, substantially reducing a patient’s quality of life. T regulatory cells (Tregs) are a class of immune cell that prevent the immune system from attacking the body. Because Tregs can prevent autoimmune disease, many attempts have been made at designing methods to generate them. As of yet, no practical and reliable means of producing Tregs has been achieved. Previous research demonstrates that Vitamin D may play a role in the Treg production process. Paxton Bach is investigating whether applying Vitamin D to the skin can be used to generate Tregs, and early results are promising. Ultimately, this research could lead to more effective, less invasive treatments for individuals living with autoimmune diseases around the world.

Testing the neural mechanisms of face processing in individuals with Autism: An MEG study

Autism is one of the most common neurological disorder affecting children, boys more commonly than girls, and usually appears in the first three years of life. It is thought that this disorder changes the way the brain processes information, causing cognitive impairments, deficits in communication and social understanding, and unusual behaviours. As a result, individuals with autism have difficulty paying attention to, and making sense of, social situations. Faces communicate a lot of social and emotional information, and are important to everyday interactions. As children develop, they typically orient to others’ faces from birth, becoming experts at recognizing faces. Conversely, children with autism are impaired at recognizing faces and facial expressions. Jennifer Barrie is using magnetoencephalography (MEG) — a non-invasive type of brain imaging that measures magnetic energy in the brain during cognition — to determine how neural processing differs in people with autism from those without the disorder. Barrie is examining when and where brain activation occurs when both groups look at faces. She anticipates that people with autism see only elements of faces, while others see the entire face, making faces easier to recognize. Using MEG, Barrie will assess whether these developmental differences can be changed with training. If so, these findings could shape future training programs that would enable people with autism to learn how to better perceive faces, improving their social and emotional functioning and quality of life.

Determination of cleavage site specificity of matrix metalloproteases by assay of a peptide library generated by enzymatic digest of a complete or partial proteome

Mass spectrometry is a technique for separating and identifying molecules based on mass. It’s an important tool in proteomic investigations, the analysis of the whole set of proteins expressed in a cell. Recent advances in mass spectrometry have enabled the identification of thousands of unknown nd uncharacterized proteins. Many of these proteins are proteases, enzymes responsible for splitting specific peptide bonds (primary links of protein structures). Patrick Beaudette is studying a protease family known as matrix metalloproteases (MMPs). MMPs regulate a variety of cell processes, from the degradation of structural proteins to the activation and inactivation of cell signaling pathways. Proteins proteolytically processed under these circumstances can have implications in a variety of disease symptoms, ranging from inflammation to tumor growth. Beaudette’s research focuses on identifying the substrates (molecules upon which enzymes act) that a particular MMP protein splits, and the mechanism by which it locates these substrates within the cell. The research may lead to a fuller understanding of the function of the MMP family of enzyes and the role it plays within a cell. The findings could contribute to the design of inhibitors for MMPs for use in therapy of cancer and other conditions.

Genetic approaches to characterize mammary stem and progenitor cells

A stem cell can both self-renew and divide to form differentiated daughter cells. In adult tissues, stem cells have the ability to generate mature cells of a particular tissue through differentiation, and to do so multiple times. Such cells were recently identified in a mammary gland, and demonstrated their capacity to regenerate their structures in other breast tissues. This was an important discovery, as it is speculated that these stem cells are central to the development of breast cancer. Because stem cells are relatively long-lived compared to other cells, they have a greater opportunity to accumulate mutations leading to cancer. Also, these cells have a pre-existing capacity for self-renewal and unlimited replication. The idea that stem cells are inherent to malignant transformation has wide-stretching implications for therapeutics, particularly with regards to drug resistance. Angela Beckett is studying the growth and differentiation of normal breast stem cells, which will provide knowledge about what drives malignant transformation and how to prevent cancer initiation. By obtaining basic information on stem cell regulation, this research is taking an important step in designing novel therapeutic approaches to their malignant counterparts, cancer stem cells.

Characterizing the role of granzyme B in atherosclerosis and hair loss in apolipoprotein E knockout mice

Cardiovascular disease is the leading cause of death in Canada. Atherosclerosis is a cardiovascular disease, in which the inside of blood vessels contain fatty growths known as plaques. Over time, these plaques become unstable and can break, resulting in blockage of blood vessels. This can lead to heart attacks, strokes and limb loss. Wendy Boivin’s research explores what makes a plaque develop, grow, and become less stable. She is focusing on a protein called Granzyme B, which is known to cause plaques. What is unknown is which of two possible approaches Granzyme B uses to induce plaque formation and atherosclerosis: either by entering blood vessel cells and killing them, or by breaking down structural proteins in the blood vessel. Wendy Boivin is studying the role of perforin, a protein that is required for Granzyme B to enter into blood vessel cells. By conducting a study that observes what happens when perforin is removed from blood vessels, she can pinpoint the pathway Granzyme B uses to cause atherosclerosis. Ultimately, this study may contribute to new therapeutic targets for combating this disease.

The role of imprinting in placentation and obstetrical complications

Up to one per cent of pregnancies in British Columbia end in stillbirth. Two conditions thought to contribute to the rate of stillbirths are pre-eclampsia and intrauterine growth restriction (IUGR). Pre-eclampsia – a form of pregnancy-induced high blood pressure – affects approximately five per cent of pregnancies, and can be life-threatening to both mother and fetus. IUGR – where the fetus is significantly undersized for its gestational age – also affects approximately five per cent of pregnancies, and is linked to health problems at birth and beyond. Abnormal placental development is thought to be responsible for many complications of pregnancy, including pre-eclampsia and IUGR. The causes underlying abnormal placental development are largely unknown. It may involve errors in DNA methylation, a mechanism used to regulate the activity of certain genes – particularly imprinted genes. Unlike the more common type of genetic inheritance where the outcome in the offspring will depend on whether a gene is dominant or recessive, imprinted genes are parent-of-origin-specific, meaning they are only expressed from either the maternal or paternal chromosome. The placenta has an overabundance of genes expressed in this way. Errors in DNA methylation and imprinting can result in changes in gene expression. Danielle Bourque’s project aims to determine if disruption of normal DNA methylation and imprinted gene expression leads to the abnormal placental development associated with pre-eclampsia or IUGR. The eventual goal is to develop a strategy to improve early diagnosis of pre-eclampsia and IUGR, which will lead to improved treatments and outcomes for both mother and baby.

Characterizing the Molecular Mechanisms of Adaptor Proteins AP-3 and AP-1B Function: An Integrated Analysis

The cell consists of many different compartments, each of which carries out a special function. A network of transport pathways moves molecules between these compartments to reach their proper location. This process, called vesicular transport, is central to the cell’s ability to grow, divide and communicate with its external environment. Receptors are dependent on vesicular transport for reaching the cell surface, where they bind factors that are essential for the cell such as hormones and nutrients. An enormous number of human diseases, including cancer, diabetes and Alzheimer’s disease, result from defects in vesicular transport. A specialized group of proteins called adaptors coordinate the wide variety of transport events within the cell. Each adaptor recognizes its own set of molecules for transport and initiates the pathway that will take them to their final destination. Adaptors cannot work by themselves; many regulators cooperate with these complexes, guiding them to the correct location and activating them for cargo binding. Helen Burston is identifying the molecules that cooperate with Adaptor Protein Complex 3 (AP-3), an adaptor required for the formation and function of lysosomes, which are required for immunity, blood clotting, and brain function. This research will help develop a better understanding of defects in neurological function and immunity.

The Role of Granzyme B in Aortic Aneurysms

An aneurysm is a permanent dilation, or ballooning, of a blood vessel or an artery to 1.5 times its normal diameter. It is usually a complication of atherosclerosis, a form of cardiovascular disease where the interior walls of blood vessels are blocked by a fatty substance called plaque. While most aneurysms are small, slow growing and rarely rupture, some are large, fast growing and at higher risk of rupturing. Aneurysm formation can result in hemorrhaging and death if not immediately repaired – the mortality rate after a rupture is 80-90 per cent. Aneurysms in the brain (cerebral aneurysms) can rupture and cause bleeding within the brain, resulting in a stroke. Ciara Chamberlain is studying a protease, Granzyme B, which is made and released by certain types of immune cells. Granzyme B may play a role in aortic aneurysms by breaking down structural proteins and causing thinning of the blood vessel wall. Building upon work in this area already conducted at the James Hogg iCAPTURE Centre, this research seeks to provide definitive evidence about the therapeutic potential for Granzyme B inhibition for the prevention of aneurysms in patients with mild or advanced atherosclerosis.

Discovery of immunogenic Salmonella peptides by immunoproteomics

Salmonella bacteria can contaminate food, causing Salmonellosis, a disease with symptoms such as diarrhea and abdominal cramps. Although treatable with antibiotics, the incidence and severity of Salmonellosis has increased over the last ten years, partially due to increased antibiotic resistance by some strains of the bacteria. Consequently, other methods of treatment or prevention are needed to better control these infections. Queenie Chan is investigating the potential to develop a vaccine for Salmonellosis. Vaccine design varies in difficulty, depending on the nature of the infectious agent. In the case of Salmonellosis, dendritic cells take up bacteria in the body and break the protein components down into small pieces (peptides) on the surface of the cells. These fragments retain the identity of the original bacteria. In theory, injecting bacterial fragments identical to those found on the surface of dendritic cells will prompt an immune response against the bacteria, without an actual infection. Chan is using an instrument called a mass spectrometer to simultaneously assess hundreds of these peptide fragments to determine which peptides elicit an immune response. Chan hopes these peptides will provide the foundation for creating a vaccine against Salmonellosis, thereby avoiding the use of antibiotic drugs that help perpetuate the growth of antibiotic-resistant bacteria.

Perinatal outcomes in a provincial based cohort of HIV positive mother-infant pairs

Every year 2.4 million HIV positive women worldwide deliver infants. In Canada, increasingly complex highly active antiretroviral therapy (HAART) regimens are widely used by pregnant woman to improve maternal health and reduce transmission to fetuses. However, there are concerns about maternal and fetal complications with HAART. Oak Tree Clinic, British Columbia’s provincial referral centre for maternal-infant care of HIV positive women and their families, maintains a longstanding comprehensive perinatal database. Tessa Chaworth-Musters is investigating, updating and expanding this database to determine complication rates in HAART-exposed pregnancies. Chaworth-Musters is adding new data fields to reflect questions in the current literature, and where available, she is making comparisons to a provincial data set from the BC Reproductive Care Program and using statistical models to determine if specific variables impact outcomes. The findings will guide Oak Tree physicians in their treatment of pregnant HIV positive women and contribute to improvement of provincial and national antiretroviral therapy guidelines and pregnancy practices. Chaworth-Musters also aims to clarify inconsistencies in already published data. Her overall goal is for the research to facilitate understanding of optimal, safe, effective and non-toxic treatment during pregnancy of HIV positive women.