Breast cancer is the second most common form of cancer. A crucial event in the development of the disease is when cells start to leave the breast tumour, enter the bloodstream and start to form a new tumour in other organs, such as the lung and bone. This process, called metastasis, dramatically reduces the patient's chances of disease recovery. Hence, in depth understanding of this process is key to successful development of novel anti-cancer drugs to provide effective treatment for cancer patients. Although the genetic changes that cause cancer to develop and metastasize are being studied, there are other molecular events that contribute to cancer. The post-translational modification of proteins — which refers to the changes that occur after the proteins are built — can dramatically alter the protein function, putting it in a different place or switching the activity on or off. One way to modify a protein is to cleave a part of it off, exposing a new protein """"tail.” Identification of the actual modification patterns in different disease situations will presumably allow for a much more precise disease diagnosis. Knowing the protein differences between metastases, which are surprisingly different from the tumours they originate from, will help to identify the fundamental causes and provide great insight into the cellular processes affected during cancer. Dr. Philipp Lange's research involves the identification of protein """"tails"""" in different cancer tumours and metastases in order to identify differences between the two. He will also introduce a new protein into the tumours that can mediate the cleavage reactions in a controlled manner, which will enable him to deduce how the individual protein components of tumours were originally connected. As a final step in his research, he will investigate the key protein modification patterns (or """"signatures"""") found in the mouse model and see if this signature exists in patient tumour samples taken from the Tumour Tissue Repository at the BC Cancer Agency. The impact of Dr. Lange's work will be twofold. First, the protein modification signatures he identifies will be used to develop a powerful new method to support earlier breast cancer diagnosis and determination of patient prognosis. Second, the identified key network modulators serve as potential drug targets for the development and testing of new breast cancer therapeutics.
Research Location: University of British Columbia - Vancouver Campus
Investigating anti-arrhythmic inhibition of voltage-gated sodium channels with unnatural amino acids and fluorescence spectroscopy
Cardiac arrhythmias are on the rise in our aging population. They are electrical disturbances in the heart that can cause a wide variety of potentially life-threatening conditions, including an increased chance of stroke or, in the case of heart failure, sudden death. Anti-arrhythmic drugs that target a particular type of protein called an “ion channel” are useful in converting these irregular heart rhythms back to a normal beating. Unfortunately, many available anti-arrhythmic drugs have serious side effects. The basic action mechanisms of anti-arrhythmic drugs are not understood, and the chemical characteristics of good/safe anti-arrhythmic drugs are not known. This makes it difficult to engineer the next generation of life-saving cardiac drugs. Dr. Stephan Pless is aiming to fill crucial gaps in our understanding of how anti-arrhythmic drugs regulate heart function. By combining cutting-edge chemical methods with computer modeling, he has already made significant progress in defining the essential characteristics of what makes a “good” anti-arrhythmic drug. His next goal is even more important, as it aims to define the precise nature of the heart receptor through which anti-arrhythmic drugs modulate electric excitability. For this purpose, he will employ novel artificial amino acids to delineate the precise location of the receptor and will use novel fluorescent probes to give us insights into the atomic-level movements of the receptor during drug binding. All of the technologies used here have been tested in other relevant systems, but never for this application; therefore, it places Dr. Pless in a position to make a substantial contribution to the cardiovascular health of Canadians.
Improving the integration of informal caregiving in long-term residential care
Informal caregiving is defined as care provided by family and friends to a relative or friend residing in a long-term residential care (LTRC) situation. The role of informal caregivers is significant. Informal caregivers contribute more than 44 million hours of care work in LTRC facilities each year; a number that will more than double to 107 million hours in 2038 (source: Canadian Alzheimer Society). These contributions are essential given the current pressures on LTRC, which include an increasingly acute and medically/socially complex resident population and staffing levels that are typically below industry standards. Dr. Jennifer Baumbusch is conducting a series of studies focused on understanding how informal caregivers currently participate in LTRC. Dr. Baumbusch is asking the following research questions in order to better understand the role of informal caregiving and to develop and refine policies and practices to improve the integration of informal caregiving in LTRC. In what ways do informal caregivers contribute to the care of their relative? In what ways do informal caregivers contribute to the care of other residents? How do the informal caregivers’ contributions affect the everyday facility routines, such as recreational activities and meal times? Research will take place on regular units and on Special Care Units for residents with Alzheimer disease and related dementias and will recognize the unique needs of this specialized population. This program will incorporate ethnographic approaches and will be guided by input from community stakeholders. Research findings will be consolidated with existing literature to provide the basis for knowledge translation activities which will include policy forums that foster a national dialogue about caregiving in LTRC, collaborative knowledge translation research, and arts-based knowledge translation approaches. The aim of this program is to improve the integration and recognize the unique contributions of both informal caregivers and formal caregivers (staff) to care provision. Generating new policy directions will contribute to more effective healthcare services within LTRC and will ultimately improve the health of aging Canadians living in LTRC.
Auto-inhibited regulatory proteins: New approaches to characterize and identify these important switches in cell communication
The impact of cancer on our society is enormous. According to the Canadian Cancer Society, an estimated 9,300 people will die of cancer in British Columbia in 2011, with 22,100 new cases being diagnosed. Despite the many different treatment options that have been developed in the past several decades, the high death rate demonstrates that new and better therapeutic approaches are necessary. Cancer is often caused by the disruption of cellular control and regulatory mechanisms. One such regulatory mechanism known as “”autoinhibition”” allows proteins in the cell to switch their own function on or off. Genetic mutations or viral infections can result in the disruption of this autoinhibitory function, which can lead to a continuous activation of these autoinhibitory proteins. This can result in cell changes and can ultimately lead to cancer. Dr. Joerg Gsponer is taking a new approach to understanding how cancer develops and, ultimately, how it may be controlled. His research group is is aiming to improve our understanding of the mechanisms of autoinhibition with the help of computational methods. His team will develop new computational algorithms that will help identifying proteins in the cell that are regulated by autoinhibition and reveal how the autoinhibition works and how it is disrupted in the disease case. Ultimately, this will further our understanding of how cancer develops and will hopefully help to identify new drug targets for cancer therapy.
Optimal Timing of Medical Decisions
Questions regarding the proper timing of various medical interventions arise frequently in health care. How often should people be screened for a type of cancer? How often should patients go for laboratory tests to measure the progress of an existing disease? What is the optimal time to initiate a therapy or to switch therapies when one appears to lose its effectiveness? These are difficult decisions because of the need to trade off costs and benefits under uncertainty. For example, screening too frequently results in high system costs as well as inconvenience (and possibly harm) to the patients being screened. On the other hand, treatment outcomes are almost always better when disease is treated earlier than later. Dr. Shechter’s research program aims to develop and apply advanced analytical techniques from the field of operations research (OR) to aid decision-making in questions of clinical timing. The methodological tools of OR were designed specifically to deal with complex decision-making under uncertainty and have been applied for more than 50 years in a variety of areas. With the growing complexity of medical decision-making and the increasing availability of patient medical data, these techniques have become extremely relevant for seeking cost-effective solutions to health-care problems. Clinical timing decisions alone provide a large class of difficult decisions that are well suited for study using these analytical techniques. Dr. Shechter’s research includes two specific projects that will analyze key timing decisions for patients with chronic kidney disease: 1) when is the optimal time to prepare an arteriovenous fistula for patients who eventually start dialysis?; and 2) how often should patients on the kidney transplant waitlist be screened for conditions that may put them at increased surgical risks should a donation become available? With a 500 per cent increase in chronic kidney disease among British Columbians over the past decade, improvements in treatment and screening policies can result in substantial health benefits to patients province-wide. Dr. Shechter will work closely with frontline decision-makers, including nephrologists and kidney transplant surgeons, to develop and validate useful data-driven decision models to address these questions.
Melanoma and neurofibromatosis: genetic diseases linked by dark skinned mouse mutants
Melanoma is the most dangerous type of skin cancer. The incidence and rate of death from melanoma is rising in Canada. Since 1988, the death rate from melanoma increased 41% in men and 23% in women, which is the highest rate of increase for any type of cancer. Melanoma is primarily caused by repeated sun damage, which leads to the accumulation of mutations in the genes that regulate the survival and growth of pigment cells in the skin. The disease has a molecular basis, so it only makes sense that a molecular approach is being taken to find new therapies to treat this deadly disease. Dr. Catherine Van Raamsdonk is taking a unique molecular approach to identify genes that may be involved in melanoma. By studying three mouse strains that have a darker dermis (the lower-most layer of the skin), Dr. Van Raamsdonk and her colleagues have discovered three genes named GNAQ, GNA11 and NF1 that are important for pigment cell growth and survival. By studying how these genes interact with each other and how they are regulated at different stages of development, she hopes to understand how they may contribute to melanoma. This work will help to reveal the molecular basis of melanoma as well as other cancers. For example, the NF1 gene is also mutated in human neurofibromatosis, a genetic disease in which patients develop disfiguring tumors and hyper-pigmentation of the skin. Dr. Van Raamsdonk and her colleagues have also discovered that GNAQ and GNA11 are mutated in 78% of human uveal melanomas, the most common type of eye cancer. This breakthrough is significant because the mutations associated with uveal melanoma were previously unknown. Dr. Van Raamsdonk is the only professor in the world examining the role of GNAQ and GNA11 in mouse pigment cells, making this work unique and essential. The information she gains may be used to prevent, diagnose, and treat different types of cancers, including melanomas.
Elucidation of the antibiotic resistance mechanisms of BlaR1 and MecR1 through structural, biochemical and cellular investigation using cell-free protein expression
The emergence of broad-spectrum antibiotic resistance is leading to the appearance of an increasing number of multi-resistant pathogenic bacteria, or “”superbugs.”” During the past decade, the superbug Methicillin-Resistant Staphylococcus Aureus (MRSA) has become a major cause of drug-resistant infectious disease. MRSA strains are resistant to all beta-lactam antibiotics, including the commonly prescribed penicillins and cephalosporins. The rapid emergence of community-acquired MRSA strains affecting previously healthy individuals outside the healthcare environment is particularly distressing, as it presents an urgent public health threat. The objective of Dr. Solmaz Sobhanifar’s research project is to investigate antibiotic resistance mechanisms in MRSA. Dr. Sobhanifar is specifically studying beta-lactam sensor/signal transducer proteins, BlaR1 and MecR1, which sense beta-lactam antibiotic levels. Understanding the structures of BlaR1 and MecR1 and how their mechanisms of action permit survival of MRSA during antibiotic treatment would considerably assist drug-design efforts. Dr. Sobhanifar is using x-ray crystallography and NMR spectroscopy to conduct the first detailed molecular structural analysis of these important drug resistance signaling proteins. Obtaining the necessary quantity of materials for structural investigation has proven notoriously challenging, so a “”cell-free”” protein expression approach will be used to obtain sufficient levels of BlaR1 and MecR1 for structural studies. This approach also facilitates selective amino acid labeling, which is important for x-ray- and NMR-based investigations. In partnership with the Centre for Drug Research and Development at UBC, the acquired structural and biochemical data will be used, in conjunction with unique small molecule and natural product chemical libraries, to screen and optimize novel lead inhibitors against BlaR1/MecR1-induced antibiotic resistance in MRSA. This will hopefully provide new therapeutic approaches to manage MRSA in the future.
Investigating the relationship between residential stability, physical and mental health, and quality of life in homeless and vulnerably housed individuals: A multi-site longitudinal study
An increasingly large number of individuals are facing homelessness and inadequate housing (i.e. living in a shelter, on the street or other places not intended for human habitation) in Canada. Annually, it is estimated that 150,000 to 300,000 individuals experience homelessness across the country. In addition, a much larger number of individuals are vulnerably housed (i.e. individuals with low or moderate income who spend more than 50 percent of their income on housing and are at risk of becoming homeless). Housing is a significant determinant of health. Compared to the general population, homeless and vulnerably housed individuals (HVHIs) have been found to be at a substantially increased risk for physical and mental illness, substance use, injuries, assaults and mortality. Furthermore, HVHIs are socially marginalized and frequently experience barriers to health care and social services. Dr. Anne Gadermann will be examining the dynamics of homelessness and housing vulnerability over time, risk and protective factors associated with onset and exiting of homelessness, and whether changes in housing status are associated with changes in physical and mental health status and quality of life. To conduct her research, Dr. Gadermann will be analyzing data from the Health and Housing in Transition study, a longitudinal multi-site cohort study of HVHIs. In this study, a representative sample of more than 1,100 HVHIs has been interviewed annually over a three-year period in Vancouver, Ottawa and Toronto. At each time point, the interview surveys assessed a wide number of variables, including demographic characteristics, housing history and quality of living conditions, physical and mental health status, family history, substance use problems, quality of life, social support, risk behaviours, health care and social service utilization, contact with the legal system, and life events. Furthermore, the interview data have been linked to health insurance databases to provide information on respondents’ health care utilization. Given the increase of homelessness and vulnerable housing in Canada, there is a greater need and demand for research evidence that can complement and expand existing policies, services and programs. The proposed research project is uniquely situated to provide such research evidence, and a special focus will be given to the dissemination of the findings in order to maximize the impact of the research findings on public policies, services and programs related to housing and health.
Advanced polymers for transfusion medicine and biology: Novel approaches for therapeutics, cell-surface engineering, biocompatible surfaces and proteomics reagents
Most simply, biomaterials are materials that interact with biological systems to perform, augment, or replace a function that has been lost through disease or injury. Biomaterials have played a critical role in the advancement of modern medical treatments and are key components in medical devices, equipment, and processes. As some examples, biomaterials are essential for the manufacture of artificial hearts, contact lenses, artificial hips, dental materials, stents, and are involved in drug delivery systems and blood storage bags. While biomaterials based on synthetic polymers are extremely versatile, they also come with significant problems. Most materials were not specifically designed for medical use, and, as a result, issues such as biocompatibility and biodegradation can create serious side-effects such as inflammation, immune reactions, local tissue damage, and ultimately the device rejection. Dr. Jayachandran Kizhakkedathu is working to address these challenges by creating new biomaterials designed specifically for use in biological systems. His research group integrates advanced polymer design and chemistry, biological analyses, and animal models to address this important problem. The knowledge and technologies developed in this program will significantly improve our understanding of how synthetic materials interact with human body. Importantly Dr. Kizhakkedathu hopes that the development of new biomaterials will help to advance medical science by inspiring innovative new treatments for cardiovascular diseases and blood disorders and by creating new diagnostic tools and devices.
Congenital Migraine Mutations alter the Calcium-Dependent Regulation of P/Q-type Calcium Channels and Affect Synaptic Plasticity
Migraine headaches affect approximately 15 percent of the Western population. However, the complicated genetic and underlying physiological basis of migraine has resulted in both slow advancement in new treatments and poor understanding of the disease at the cellular level. Familial Hemiplegic Migraine (FHM) is a type of migraine with similar clinical features to typical migraine, and likely with similar cellular mechanisms, but with well-understood genetics. FHM has become a leading model for studying typical migraine. FHM is clinically characterized by migraine headaches, usually preceded by visual or auditory auras (sensations), and accompanied by hemiparesis (one side of the patients body undergoes varying degrees of paralysis during the migraine attacks). The migraine symptoms can last from a few minutes to several days. Approximately 50 percent of patients with FHM have mutations in the CACNA1A gene, which codes for a type of calcium channel protein that is primarily responsible for facilitating communication between neurons in the brain. Paul Adams’ research focuses on identifying FHM genetic mutations in patients and then introducing those mutations into cloned calcium channel genes. The effects of the FHM mutation on calcium channel properties can then be studied by introducing the mutated channel into a human cell line and then studying the channel using electrical recording techniques. Additionally, the effects of FHM mutations on communication between neurons in the living brain will be studied in mice that have been genetically engineered to contain human FHM mutations in their CACNA1A gene. The results of Adams’ research will provide a better understanding of the molecular mechanisms behind FHM, and thereby contribute to the development of more effective therapies for all types of migraine headaches.