Each year in Canada about 100,000 people develop sepsis—a severe illness caused by the presence of bacteria in the bloodstream. The condition causes blood pressure to drop, resulting in shock and may lead to multiple organ dysfunction and eventually death. With a mortality rate of 30 and 65 per cent respectively, sepsis and septic shock cause more deaths annually than heart attacks. Inflammation and immune response to infection varies greatly between patients. Some inflammation is a normal defense against infection. However, if inflammation is excessive, white blood cells and other cells can spill into the circulatory system and damage healthy organs. Continuing her previous MSFHR-funded research, Ainsley Sutherland is studying whether the genes that recognize bacteria and viruses play a role in determining which patients will develop the excessive inflammation that can lead to sepsis. This understanding could lead to the development of drug therapies for patients at higher risk of sepsis, and the avoidance of unnecessary drug side effects in patients who are not at risk.
Research Location: Providence Health Care
Functional analysis of interferon inducible protein 10 gene in Coxsackievirus B3-induced myocarditis
Coxsackievirus B3 (CVB3) is the leading cause of viral myocarditis, an inflammation that can so severely damage the heart that a heart transplant becomes the only treatment option. Previous studies have identified 28 up – or down – regulated genes in CVB3-infected mouse hearts, but the functions and mechanisms of the host gene regulation in the progression of CVB3-induced myocarditis are not clear. Ji Yuan is further analyzing the role of host gene alteration in viral myocarditis by investigating the IP10 gene, believed to be the most crucial up-regulated gene. Her objective is to define the functional role of IP10 and trace the cascade of events precipitated by its up-regulation which result in major damage to the heart. By conducting these experiments, she will not only have a better understanding of the molecular mechanisms of viral myocarditis, but also may discover potential targets for gene therapy or new diagnostic tests for this heart disease.
Vascular endothelial growth factor induces endothelial cell hyperpermeability to low density lipoproteins in atherosclerotic disease
Coronary artery disease (CAD) and transplant associated-CAD are caused by a reduction or complete blockage of blood flow in blood vessels of the heart, which results in tissue death due to lack of oxygen. CAD is the leading cause of heart attacks, and transplant associated-CAD is the leading cause of organ failure one year after transplantation. Both diseases are characterized by abnormalities in blood vessel walls – abnormalities that result in the accumulaton of lipids and other blood components inside vessel walls. This causes them to thicken which acts to constrict blood flow. The endothelium is a blood vessel lining that serves as a barrier between the blood and tissue and also has a role in directing the transport of ions, lipids and proteins. Previous research has shown that vascular endothelial growth factor (VEGF), one of the most potent inducers of vascular permeability, is upregulated in these diseases. Brian Wong is working to determine the specific mechanisms by which VEGF induces this effect. He hypothesizes that the abnormal production of VEGF in CAD and transplant associated-CAD compromises endothelial barrier function, resulting in the increased passage of lipids and proteins into the vessel wall. Ultimately, he hopes to determine the therapeutic potential of blocking VEGF production in order to reduce lipid entry and accumulation in the vessel wall and prevent these diseases.
Treatment readiness and motivation research: improving quality of care and health outcomes
Treatment refusal, dropout, and relapse are common in individuals with eating disorders, resulting in physical and emotional costs to the patient, societal costs to the community, and economic costs to the health care system. Dr. Josie Geller’s previous research has shown that a patient’s readiness to change is the best predictor of clinical outcomes in the eating disorders. However, there remains a need for validated assessment tools and guidelines to determine which patients are ready for what type of treatment; development and evaluation of interventions that enhance readiness for treatment; and dissemination of findings from this research to clinicians and to community support providers on the benefits of matching treatment to patient readiness. The primary objective of Dr. Geller’s research is to use a patient-focused approach that draws upon applications of psychological models of readiness and motivation for change to improve health service delivery, utilization, and quality of care. Her program aims to provide a set of guiding principles for efficient, cost-effective care that has broad applications to the health care system, including eating disorders, HIV, Hepatitis C, and other emerging priority areas.
Access to kidney transplantation in British Columbia and Alberta
In Canada, there are large regional disparities in the waiting times for kidney transplantation. Previous studies show that these disparities cannot be explained by differences in the rate of organ donation or the incidence of kidney disease; instead, they may be the result of practice differences in referral or acceptance of patients for transplantation. Unlike waiting lists for most other medical services, increased waiting times for transplantation are clearly associated with loss of life. Currently, there is no formal, national system to ensure that medically eligible patients have equal access to transplantation across Canada. Very little research has been conducted regarding regional disparities in access to transplantation. To gain insight into the cause of these differences, Dr. John Gill is following a group of new dialysis patients in BC and Alberta to determine if there is a difference in referral for kidney transplantation or acceptance for transplantation within one year of starting dialysis. He will investigate the reasons why patients who are medically eligible for transplantation may not be referred for transplant, and document provincial differences in the time required to complete the transplant assessment and to activate a patient onto the transplant waiting list. Ultimately, this research will contribute to enhanced patient and physician education, better implementation of protocols to ensure that patients are appropriately referred, and new strategies to minimize regional disparities between provinces.
Tissue microarray analysis of Type 1 growth factor receptor family expression by human breast and colorectal Cancer: prognostic significance and treatment implications
Breast cancer and colorectal cancer are leading causes of cancer-related deaths worldwide. The identification of specific tumor characteristics that would allow for an accurate prediction (prognosticators) of disease course and response to treatment would represent an important advancement in the management of these common malignancies. Unfortunately, no currently known disease prognosticators are reliable in predicting clinical course, or identifying the treatment that would be of greatest benefit to an affected individual. Recently the detection in some tumours of HER1 and HER2 proteins – members of the type 1 growth receptor family (T1GFR) – have shown promise for helping predict patient outcomes and in determining which tumors respond best to specific therapies. These proteins have also recently been used as targets for newly developed drugs to treat these cancers. The expression of the entire T1GFR family (HER1, HER2, HER3, and HER4) by breast and colorectal tumors, and their potential usefulness in predicting disease outcome and patient response to specific treatment(s) has not been explored. Dr. Sam Wiseman is evaluating the expression of the entire T1GFR family in a group of 4500 breast cancer and 500 colorectal cancer samples to determine its relationship to patient treatment and outcomes. His study will be carried out utilizing tissue microarrays, a methodology that allows for the rapid evaluation of large numbers of tumors for molecular markers. The results of this study may lead to improved disease prognostication, outcome prediction, and therapy selection for people diagnosed with breast or colorectal cancer.
Injection site infections of injection drug users in Vancouver's downtown eastside
In addition to other serious health risks experienced by Canada’s estimated 125,000 injection drug users, individuals who inject drugs commonly develop infections at the site of injection, such as abscesses and cellulitis (infection of the skin’s deeper layers). Previous studies have shown these injection site infections account for the majority of admissions to emergency departments and hospital beds in Vancouver. Treatment is inefficient and costly, and these infections can lead to more severe complications, including bone infection, amputation and death. Surprisingly, there has been little research on preventive measures. Now, Elisa Lloyd-Smith is studying which individuals are at increased risk for injection site infections, and what preventive measures and treatments are most effective. She is also assessing whether the supervised injection facility in Vancouver’s Downtown Eastside community, the first in North America, reduces hospitalizations due to injection site infections. This is the first study anywhere in the world to evaluate the impact of a safe injection site on infection rates. Elisa’s research will identify preventive measures to reduce the incidence of injection site infections, improve health outcomes among injection drug users, and reduce health care costs.
Role of the Ubiquitin/ Proteasome pathway in Coxsackievirus-Induced Myocarditis
Myocarditis is an inflammatory heart disease caused by the coxsackievirus that enlarges and damages the heart and may lead to sudden heart failure. In severe cases, heart transplant is the only treatment for this condition. When the infection occurs in newborns and children the outcome is frequently fatal. Even with non-lethal infections, long term heart failure is a common result. Research has shown that inhibiting the major intracellular pathway for protein degradation, called the ubiquitin/proteasome pathway, limits the ability of the virus to multiply and infect other cells. The proteasome are immune cells that accumulate and destroy unwanted or damaged proteins. The ubiquitin is a molecule that latches onto damaged or mutated proteins and flags them for destruction by the proteasome. By blocking this pathway, research has shown that the coxsackievirus can be prevented from producing proteins, which may affect the ability of the virus to replicate. Guang Gao is studying the importance of the ubiquitin/proteasome pathway in coxsackievirus replication and in virus-induced acute heart injury and chronic heart failure. His studies will provide important insights into the interaction between the virus and the ubiquitin/proteasome system and ultimately may lead to the development of more effective methods of preventing or treating myocarditis.
Health Research of Vulnerable Urban Populations
Up to half of all Canadians with HIV also have hepatitis C, with co-infection highest among injection drug users. Dr. Anita Palepu is researching the impact of drug and alcohol use among people co-infected with HIV and hepatitis C on their adherence to HIV treatment and on treatment outcomes. Dr. Palepu, who focuses on health and social problems faced by vulnerable urban populations such as drug users and homeless people, is also examining the role of addiction treatment in clinical outcomes. In a related project, she is conducting a quality of life study with vulnerable populations such as injection drug users, homeless people and street youth to assess the effectiveness of interventions intended to improve their lives. Dr. Palepu is also part of a national network of researchers evaluating the effects of programs designed to prevent homelessness, or help people exit homelessness, on the health of those considered “hard to house.” The research could inform health and social policies and ultimately help improve the health of vulnerable urban populations.
Contribution of the ubiquitin/proteasome pathway to coxsackievirus-mediated myocarditis
Myocarditis, an inflammatory heart disease caused by the coxsackievirus, can lead to a dilated (enlarged) heart, which can result in sudden heart failure. A heart transplant is the only treatment for this condition. The proteasome is a cellular garbage collector that accumulates and destroys unwanted or damaged proteins. Ubiquitin is a molecule that latches onto damaged or mutated proteins and flags them for destruction by proteasomes. In earlier research, Dr. Honglin Luo showed that blocking the ubiquitin/proteasome pathway prevents the coxsackievirus from producing proteins, which may affect the ability of the virus to replicate. Now Dr. Luo is further investigating the effect of the ubiquitin-proteasome pathway on replication of the coxsackievirus and development of myocarditis. The research could confirm that inhibiting the pathway limits virus replication and prevents abnormal protein degradation, which could lead to new treatments for myocarditis that reduce progression of the disease to heart failure.