There is a growing prevalence of type 2 diabetes. It has been estimated that more than 20 million people have the disease in the United States alone. Type 2 diabetes is a disease characterized by resistance of our bodies to insulin, a hormone needed for normal metabolism of carbohydrates, fats, and proteins. This resistance leads to prolonged elevation of blood sugar levels, eventually giving rise to the diseased state. Understanding what events lead to insulin resistance is an intense topic of research. Nevertheless, the precise molecular mechanisms by which insulin resistance arises still require delineation in order to fully understand the disease Building on his MSFHR-funded Master’s research, Matthew Macauley is investigating what the role of proteins modified by a sugar known as GIcNAc have in causing insulin resistance. One hypothesis is that high levels of glucose over a long time period may increase GlcNAc modification and that this in turn results in insulin resistance. Macauley is using an enzyme inhibitor of O-GlcNAcase to artificially create elevated levels of GlcNAc in animal models to determine if insulin resistance and type 2 diabetes ensue. Using this same enzyme inhibitor, Macauley is also conducting a separate study to increase GIcNAc attached to tau, a key protein involved in the development of Alzheimer’s disease. The goal of this study is to determine if the inhibitor can prevent or delay the onset of Alzheimer’s in an animal model.
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Goal adjustment processes and caregiver health: Can giving up be a good thing?
Mounting evidence indicates that caring for a family member with a chronic illness not only reduces the quality of life for the caregiver, it also increases the caregiver’s risk of becoming ill. Little is known about the specific mechanisms by which caregiving impacts health and well-being. One important factor may be the caregiver’s ability to adjust personal family and career goals to meet the demands of the difficult situation. If a caregiver is able to let go of goals set before the diagnosis, such as getting a promotion at work or building a vacation home, he or she may have an easier time adjusting to this new role, and in turn, experience reduced distress and better physical health. Teresa Marin is examining the impact of tendencies to adjust goals on both psychological and physical well-being. Once she has determined the relationship between goal adjustment and health in the context of caregiving stress, it will be possible to apply this knowledge to clinical interventions designed to foster better coping skills among caregivers. This research follows Marin’s MSFHR-funded Master’s work, in which she analyzed the mental and physical health of spouses caring for cancer patients to determine the daily impact of expressing or suppressing their emotions.
Links between Patellofemoral Biomechanics and Osteoarthritis
One in ten Canadians suffers from osteoarthritis, an incurable disease that causes pain and limits motion in joints. It occurs most often in the knee joint; the patellofemoral joint, which is located at the juncture of the kneecap and thigh bone, is involved in half of these cases. Emily McWalter’s research is focused on improving the diagnosis and treatment of patellofemoral osteoarthritis. It is widely believed that biomechanical factors, such as abnormal joint motion and excessive force exerted on bone and cartilage are related to the onset and progression of osteoarthritis. While treatment focuses on correcting abnormal joints through surgery or physiotherapy, these treatments do little to slow progression of the disease. That’s likely because the procedures do not correct all of the biomechanical factors contributing to the damage. With recent advances in MRI imaging, it’s now possible to study biomechanical factors and cartilage degeneration simultaneously. Emily McWalter’s research is focused on developing better methods of detecting and identifying the causes of cartilage degeneration earlier. She is currently working to develop and validate a tool that can estimate the pressure that develops on the surface of cartilage, with a view to using this information to determine if areas under abnormal levels of pressure are at greater risk for degeneration. If successful, this tool will be a valuable asset in understanding the onset and development of patellofemoral osteoarthritis and in assessing the effectiveness of surgeries and other biomechanics-based treatment strategies.
Action Schools! BC: The effect of a school based physical activity model on risk factors for cardiovascular disease in Aboriginal children
Cardiovascular disease (CVD) is a chronic condition that can lead to heart attack and stroke. CVD costs the BC health care system approximately $2.5 billion a year. Sadly, the onset of cardiovascular disease often starts in childhood. About 50 per cent of North American children exhibit one or more risk factors for CVD and many children and adolescents exhibit multiple risk factors. These statistics are worrisome because the severity of CVD increases with the number of risk factors, and risks during childhood tend to track into adulthood. As a result, these children are susceptible to developing cardiovascular disease as adults. Previous research has linked higher levels of physical activity during childhood to a lower risk for CVD as adults. Lindsay Nettlefold is examining the prevalence of CVD risk factors in children and whether differences exist between girls and boys and between children of different ethnicity. She is also studying whether a school-based physical activity program can reduce the level of risk factors for cardiovascular disease in children. The goal to develop an effective program that could be used to improve cardiovascular health in children will prove beneficial in helping to prevent the development of disease later in life.
The characterization of KiSS1 and GPR54 in breast cancer and other hormonally responsive cancers
Cancers whose growth is influenced by sex hormones, such as estrogen and testosterone, form the largest group of cancers that affect Canadian men and women. Breast cancer remains the second most common cause of cancer death among women in North America, and prostate cancer rates third for men. While there have been advances in treatment, many of these patients will succumb to their disease when tumors metastasize (spread to other organs or tissues in the body). The KiSS1 and GPR54 genes have demonstrated the ability to prevent metastases from developing. While the importance of KiSS1 and GPR54 are being studied in other cancers, little has been done to investigate the involvement of these two genes in clinical breast and ovarian cancers, and no studies have been conducted in prostate cancer. Building on her MSFHR-funded Master’s research, Leah Prentice is investigating whether KiSS1 and GPR54 have dual roles as both tumor promoters, via their involvement in hormonal processes, and also as suppressors of metastasis. By understanding the anti-metastatic mechanism of these two genes, Prentice hopes to contribute to the development of more targeted therapies and diagnostic tests that would allow for earlier detection of these potentially life-threatening cancers.
Targeting Lung Cancer Genomics: A Whole Genome Approach to Predicting Drug Response
Lung cancer is the leading cause of cancer death worldwide, with five-year survival rates among the lowest for commonly diagnosed cancers. The high mortality rate is partially due to the lack of effective treatment options since surgery and chemotherapy are common options, yet non-curative. The epidermal growth factor receptor (EGFR) gene is overexpressed in a majority of lung cancers. Researchers recently discovered a new drug designed to target the product of this gene. Although the drug didn’t benefit the majority of patients, a positive response was often seen in non-smoking women of Asian descent. At the BC Cancer Research Centre, Trevor Pugh is researching why this drug works for this subgroup and not for other patients. Using tumour samples and patient outcomes data, he is searching across the entire genome to pinpoint specific genetic features shared by drug-responsive tumours in patients with lung cancer. Ultimately, his work could result in improved diagnostic tests for predicting who will benefit from specific therapies, and new candidates for gene-targeted cancer drugs.
Characterization of retrograde transport machinery and its relationship to amyotrophic lateral sclerosis (ALS) using the yeast model system
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a rapidly progressive motor neuron disease that causes paralysis and is ultimately fatal. In ALS, motor neurons (nerve cells) are impaired and eventually die. This process breaks the connection between voluntary muscles, which individuals control, and the brain. Other types of brain cells are unaffected, which means patients become paralyzed but their cognitive abilities remain intact. Specialized transport proteins carry survival signals from one end of the neuron to the other. In a mouse model of ALS, the cause of motor neuron disease was found to be due to a mutation in the Vps54 transport protein. In all types of cells, material is transported in a specialized container called a vesicle. In her research, Nicole Quenneville has found that a particular region of the Vps54 transport protein is involved in recognizing the surface of vesicles. It’s this region that is mutated in the mouse model of ALS, suggesting that faulty recognition and transport of these vesicles may lead to motor neuron disease. Using a yeast model, Quenneville is further investigating whether the Vps54 mutation causes transport defects, and whether the mutation changes the interactions that the Vps54 protein has with other proteins. As well, she aims to identify genes and proteins that work with Vps54 to transport molecules within the cell. Quenneville hopes her research will help identify candidate genes for novel therapies, diagnosis, and assessment of susceptibility to ALS.
Development of Fluorinated Carbohydrates for use as Positron Emission Tomography Imaging Agents and Pharmacological Chaperones in the Treatment of Lysosomal storage diseases
Lysosomal Storage Diseases (LSD) are a rare group of more than 40 disorders, including conditions such as Gauchers and Tay Sachs disease, in which a genetic abnormality leads to the buildup of naturally occurring compounds throughout the body. This process may lead to a variety of symptoms including skeletal defects, heart problems, mental retardation, and death. The diseases can be treated by enzyme replacement therapy, in which a missing enzyme is injected into the bloodstream so it can move into cells to alleviate the buildup of these compounds. However, the therapy is extremely expensive and cannot be used to alleviate neurological symptoms. Brian Rempel is developing imaging agents for Positron Emission Tomography (PET), a highly specialized technology that produces powerful images of the body’s biological function. Using PET with enzyme replacement therapy would enable imaging of an injected enzyme and tailoring of the dose to the individual patient, which could reduce the costs of the therapy. As well, PET imaging would allow for a better understanding of how the enzyme is distributed throughout the body. Rempel is also investigating the development of pharmacological chaperones, molecules that bind to the mutant enzyme that is deficient in LSD patients. The molecules help the enzyme migrate to the correct cellular compartment where it can function normally, with the aim of enhancing the patient’s own naturally occurring enzyme levels. Pharmacological chaperones would be a fraction of the cost of enzyme replacement therapy.
Regulatory mechanisms of the anti-apoptotic NAIP gene during cellular stress and malignancy
Apoptosis, or programmed cell death, is a critical physiological process that is turned on and off as appropriate to eliminate abnormal cells. When this switching process goes awry, it can lead to a variety of diseases including cancer. The genetic mechanisms that inhibit activation of the apoptosis protein (IAP) family include molecules that sequester key enzymes necessary for turning on and sustaining the process of programmed cell death. Neuronal apoptosis inhibitory protein (NAIP) is particularly interesting because expression of NAIP is reported to be highly elevated in various leukemias. In addition, NAIP is commonly deleted in the most severe cases of spinal muscular atrophy (SMA) and studies also have shown that a specific copy of this gene is required to suppress replication of the bacterial pathogen that causes Legionnaire’s disease. Researchers have also proposed that expression of NAIP in neurons of patients with Alzheimer’s disease can limit the high levels of cell death. Mark Romanish is studying the expression and regulation of NAIP to better understand its role and function in health and disease. Apoptosis is a highly regulated process receiving many activating and inhibiting signals, but the final outcome relies on which signals tip the scale. Therefore, the question of gene regulation becomes particularly important since those genes capable of rapid activation are more likely to influence the ultimate fate of a cell.
Adaptive resistance to aminoglycosides in Pseudomonas aeruginosa
Cystic fibrosis (CF) is the most common genetic disorder among young children in Canada. CF affects the lungs and digestive system of almost 70,000 children and adults worldwide. A defective gene causes the body to produce thick, sticky mucus that clogs the lungs leading to frequent lung infections and obstructs the pancreas stopping enzymes from helping the body break down and absorb food. Pseudomonas aeruginosa is a bacteria commonly associated with both hospital-acquired infections and chronic lung infections in people with CF. Although these lung infections can be temporarily suppressed, they are never completely cured and are eventually fatal. Kristen Schurek is investigating how P. aeruginosa develops resistance to the class of inhaled antibiotics called aminoglycosides that are used to treat lung infections in CF patients. Schurek believes these antibiotics trigger the organism to adapt its genetic physiology causing small, incremental increases in resistance over time. As a result, the bacteria gradually develop the ability to persist in the presence of the antibiotics. She will determine how these antibiotics cause the bacteria to adapt, and which genes in P. aeruginosa contribute to antibiotic resistance. This knowledge could lead to better methods of administering antibiotics to prevent drug resistance in people with cystic fibrosis.