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.
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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.
Effect of long term air pollution exposure on childhood respiratory diseases in the Georgia Basin: A cohort study
Asthma is the most common chronic disease in childhood. Long term studies indicate predisposition to asthma develops in the first three to five years of life. Recent evidence suggests exposure to air pollution from traffic is associated with new cases of asthma. However, the long-term impacts of air pollution exposure and whether this exposure causes asthma are unclear. Nina Clark is investigating the association between exposure to air pollutants and childhood respiratory diseases in southwestern BC. Using the BC Linked Health Database that connects various data sources to provide individual level health outcome data, Clark is tracking the exposure and health outcomes of approximately 120,000 children who were born in the region over the four-year period beginning in 1999. She will examine resources including maps detailing air pollution concentration, medical services plan billing records and hospital discharge records. Clark will also look at variables such as age, gender, birth weight and socioeconomic status. She hopes her research will lead to targeted reductions of air pollution exposure, such as zoning or land use restrictions to limit exposure of children, and help provide focus for future interventions and policies.
Characterization of a new checkpoint in hematopoietic stem cell development
Blood cells are critically important to human health and a significant perturbation of blood production is life-threatening. In addition, the transformation of blood cell precursors leads to fatal leukemias, lymphomas and myeloma that remain difficult to treat and are often fatal within a few years of diagnosis. All blood cells must be produced from a common pool of self-maintaining cells called blood stem cells. Understanding the regulation of these cells and their immediate derivatives is critical because they are thought to be the origin of most blood cancers and it is the transplantation of these cells that is required to rescue the blood-forming system in patients who can benefit from treatment with an otherwise lethal dose of chemotherapy or require replacement of a defective blood-forming system. Although the use of blood stem cell transplants can be life-saving, its application is still limited. A major barrier to more widespread use is the extremely limited number of blood stem cells in the tissues where they are produced, and our inability to grow or expand these cells in tissue culture. Previous research has demonstrated that as they develop from fetal to adult cells, blood stem cells undergo an abrupt change that reduces their capacity to expand. Michael Copley’s research at the Terry Fox Lab focuses on improving our understanding in molecular terms of the mechanism that switches the ability of blood stem cells to expand that occurs shortly after birth. This could lead to the development of ways to block or reverse the switch, so that adult stem cells can be made more effective. It could also lead to an increased understanding of why different types of leukemias and other early onset blood disorders develop in children and adults.
Remaining patient: Transforming the practices of health care to promote positive outcomes for teen mothers and their children
Teen pregnancy is a health issue affecting Canadian youth, particularly vulnerable teens. Unfortunately, teen mothers typically do not access health care regularly which hinders their ability to receive necessary information about both prenatal and maternal health. Without effective and early intervention, young mothers and their children have ongoing health, social and education issues that strain the health care system. While researchers have differing opinions about the impact of age on these health outcomes, most research defines teenage pregnancy as a health and social problem. Genevieve Creighton is studying whether the concept of teen mothers as “ill” stigmatizes teen mothers, making them reluctant to access the health care system for fear of being judged by health care workers and educators. Creighton is working with pregnant and parenting teens and their health care providers to determine whether certain attitudes and practices have a negative impact on their relationships and how these can be transformed. This information could help health and social service providers design more effective programs for teen mothers and other vulnerable populations.
T regulatory cells and T helper 17 cells: interactions between two distinct T cell subsets important for immune homeostasis
The immune system tries to maintain an optimal balance between immune responses to control infection and tumour growth, and reciprocal responses that prevent inflammation and autoimmune diseases. Impaired immune responses, such as those that occur with autoimmune disorders (multiple sclerosis, type 1 diabetes) and organ transplant rejection, result when a person’s immune system mistakenly attacks normal cells. Currently, patients afflicted with this condition must follow a strict regime of immunosuppressive drugs for the rest of their lives. However, these treatments seriously compromise the body’s ability to fight infection and also increase the risk of developing cancer. Sarah Crome is studying the role of a newly discovered class of cells, called T regulatory (Treg) cells in immune system response. She is studying how Treg cells suppress other immune cells and essentially act as a “brake” for the immune system. She is also examining how a subset of T cells, called T helper 17 cells, cause harmful immune responses that result in the rejection of transplanted tissues. A better understanding of these cells and the interactions and factors that regulate their differentiation and function, may lead to more effective treatments for organ transplantation and autoimmune diseases without compromising normal immune function.
The role of Na+/H+ exchangers (NHEs) in pH regulation and brain function
The regulation of pH (a measure of acidity or alkalinity) is a highly sophisticated and tightly controlled process that is extremely important for proper brain function. Abnormal fluctuations in the pH of neurons (nerve cells) may be involved in the development of many neurological disorders such as epilepsy. Sodium-proton exchangers (NHEs) are membrane proteins that play an important role in maintaining and regulating cellular pH. Two forms of these proteins in humans, NHE1 and NHE5, are found at high levels in the brain. Graham Diering is investigating the exact function of NHE5, the only NHE that occurs almost exclusively and at high levels in the brain. NHE5 has been linked to familial paroxysmal kinesigenic dyskinesia (PKD), a neurological movement disorder. However, the precise involvement of the protein in PKD, and its role in proper brain function, are unknown. Diering is researching NHE5 in different brain structures, including mature and developing tissue, and examining the protein at the cellular level to determine where it may be active in nerve cells. An enhanced knowledge of the mechanisms in nerve cells that regulate pH could increase understanding of the factors that govern brain function, both in the normal and diseased state. As well, an analysis of specific molecules involved in this process could contribute to development of diagnostic and therapeutic strategies for treatment of neurological disorders.