Investigating the structure and function of the PIKK family of protein kinase

Many major chronic diseases, including cancer, Type 2 diabetes, and neurodegenerative disorders, are caused by perturbations in the internal communication network of the cells within the body. Signaling molecules, which are an important part of the intracellular communication network, coordinate different processes by relaying signals to switch on or off the proper sets of cellular machineries at the appropriate time. By understanding how these signaling molecules work, scientists hope to understand the molecular basis of different diseases and how to treat and prevent these diseases.

One important group of signaling molecules are the PIKK kinases. PIKK kinases are responsible for regulating cell growth and initiating responses to DNA damage, processes that are often disrupted or exploited in cancer formation and progression. Although recent research has identified the different proteins and protein complexes that PIKK kinases receive signals from or transmit signals to, exactly how these communication events occur at the molecular level remains poorly defined.

Dr. Calvin Yip's research program aims to understand the role of PIKK kinases in cancer progression. He is characterizing the three-dimensional structural and biochemical details of these molecules using an advanced imaging technique known as single-particle electron microscopy. Dr. Yip has obtained the first information on the 3D shape of a signaling complex formed by TOR, a member of the PIKK kinase family. With this foundation, he will use an interdisciplinary approach to combine cutting-edge electron microscopy technology and other biochemical and molecular biology methods to further determine how the TOR signaling complex receives and integrates information and how it sends signals to its targets.

Dr. Yip hopes that by focusing on how TOR and other PIKK signaling molecules carry out their biological activities, he will gain a deeper understanding of the fundamental processes of cell growth regulation. This will help pave the way for the development of new therapeutic approaches against cancer.

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.

Effects of Adult Aging on Neural Control and Muscle Fatigue

Individuals 65 years of age and older constitute the fastest growing age group in Canada. With natural adult aging, the neuromuscular system (the muscles of the body and the nerves that supply them) undergo degenerative changes that are characterized by reductions in strength and power due to decreased muscle size. This age-related muscle weakness and overall decline in muscle function is referred to as sarcopenia. Sarcopenia not only interferes with tasks as lifting and carrying groceries, navigating stairs, and performing smooth complex movements, it is highly linked to physical disabilities and risk of falls. Sarcopenia is caused by a decrease in the number and function of motor units (MU), which consists of a single nerve branch and all of the muscle fibres it supplies. During the aging process, some of the MUs die off, while other MUs change structurally to compensate. As a result, there are fewer MUs present, but each one supports more muscle fibers. This MU remodeling process is a compensatory mechanism that acts to maintain muscle strength until a critical threshold is reached and strength decreases at an accelerated rate, usually by the eighth decade of life.

To understand the underlying biological mechanisms of MU remodeling, Dr. Brian Dalton is using a technique called single-unit microneurography. This research tool uses tiny electrodes inserted through the skin and into a peripheral nerve to stimulate and record signals from individual MUs. Using this technique, he will measure the integrity of functioning MUs in aged adult volunteers to determine if MU remodeling impairs neuromuscular function and muscle performance in the older adult. This work will help build a more comprehensive understanding of the neuromuscular system, specifically the process of sarcopenia and how it impacts natural adult human aging. The information gained from this study will aid in the design of functional training programs to improve and maintain muscle function — and quality of life — in older adults.

Improving Enzymatic Removal of Major Blood Antigens

Blood transfusion is a critically important medical procedure used to treat blood loss due to trauma or during surgery; it is also used in the treatment of chronic blood disorders such as thalassemia, sickle-cell disease and other forms of anemia. Due to the presence of blood antigens, however, careful blood typing is necessary to avoid the adverse and sometimes fatal reactions that may result from a mismatched blood type during transfusion. The A and B blood antigens are considered the most clinically important blood antigens. These antigens consist of carbohydrate (sugar) molecules attached to the surface of blood cells. People with type O blood lack the A and B antigens on their red blood cells and thus are often considered “”universal donors”” (not accounting for minor antigens), yet units of type O blood are frequently in short supply due to high demand. The use of enzymes to remove A and B antigens is a potential means of generating universal blood donor cells from blood types other than O. Dr. David Kwan’s research aims to investigate methods for the enzymatic removal of blood antigens from blood cells. Although enzymes that remove the A or B antigens to convert red blood cells have been discovered, they have low efficacy. Recently a new enzyme called EABase was discovered, which can efficiently remove the B antigen but only slowly removes the A antigen from red blood cells. The primary focus of Dr. Kwan’s work will be to engineer the EABase enzyme using “”directed evolution”” techniques to improve the efficiency of EABase in removing blood antigens so that it may be a more efficient catalyst for the conversion of A-, B- and AB-type red blood cells into “”universal blood cells.”” A secondary focus, in collaboration with the Centre for Blood Research, will test the use of polymer additives to enhance the rate of enzyme action. Over 15 million units (approximately 450 ml per unit) are collected for preparation of blood products in Canada and the United States per year. The ability to generate universal blood donor cells would be a breakthrough development, allowing transfusion without the need to find a positive match and tremendously improving the supply of blood while increasing the safety of blood transfusions.

Adherence to Immunomodulators in Multiple Sclerosis: Prevalence and Clinical Impact (The AIMS Study)

Taking prescribed medications as intended, or “”adherence”” is an important strategy for the management of chronic diseases. Half of the individuals with a chronic disease have poor medication adherence, and research has shown that people with poor medication adherence often have more health problems, higher hospitalization rates and a higher risk of death. Not surprisingly, medication non-adherence is extremely expensive, and is estimated to cost the Canadian health care system $8 – 10 billion every year. With an estimated 75,000 Canadians affected, and three new people being diagnosed every day, Canada has one of the highest rates of MS in the world. Multiple sclerosis (MS) is a chronic disease of the brain and spinal cord, leading to disability, severe fatigue and coordination problems. Although there is no known cure, immunomodulatory drugs (IMDs), are now commonly prescribed for MS and can lead to a substantial improvement in the health of people with MS. The benefits of IMD therapy might not be realized in people who have poor adherence; currently very little information is known about adherence to these medications. Dr. Charity Evans is working to determine how many individuals with MS have good adherence to these medications, and if people with poor adherence have higher rates of hospitalizations or worsening of the disease. She will also work to identify any time periods during therapy when an individual is more likely to be non-adherent to their IMD. Dr. Evans will be using administrative health data from three provinces (British Columbia, Saskatchewan and Manitoba), and will be studying those individuals with MS who have received an IMD between 1995 and 2008. The results of this research study will be important to determine the impact that non-adherence may have on patient health outcomes in MS, and will also help identify factors to optimize adherence to MS therapies. These methods will also be applicable to the study of adherence in other chronic diseases requiring similar drug therapies.

Survival and Cause of Death in the British Columbian Multiple Sclerosis Population

Multiple sclerosis (MS) is a relatively common neurological disease. Because of its chronic nature and because it typically first appears in people in their mid 20s to 30s, people with MS are usually expected to live for many years following disease onset. Little is known about survival expectations, predictors of long-term survival, how survival is influenced by MS drug therapies, and causes of death in this population. Ever since immunomodulatory therapies first became available to Canadian MS patients in the mid 1990s, there has been a rapid uptake of these drugs. These medications appear to be at least partially effective in modifying some aspects of the disease, such as relapses, but they are associated with significant side effects, require frequent injections, and are expensive. The long-term impact of treatment is unknown and opportunities to study treatment-naïve patients have diminished over the years, as there are fewer patients with MS who have not taken these therapies. In British Columbia, we have a valuable data resource that includes both unexposed (untreated) and treated MS patients.

Dr. Elaine Kingwell is combining several large, powerful, clinical and administrative longitudinal datasets, including the population-based BC MS clinical database (containing data from approximately 7,000 MS patients over a 30-year period), BC Ministry of Health medical services plan registration data, BC Vital Statistics death data and BC Cancer Agency data. She will use this data set to determine the long-term health impacts of MS and how they are influenced by immunomodulatory drugs. She will specifically compare the causes of death (including cancer, suicide, heart disease and infection) between people with MS and the general population.

Dr. Kingwell will also investigate cancer survival of MS patients in comparison to the general population, which is an area of some controversy. She will determine how frequently MS is listed as an underlying or contributing cause of death, which will help to facilitate planning and interpretation of population-based studies of MS mortality trends. Findings from this study will further our understanding of the role that MS plays in long-term health outcomes, such as cancer survival, and will broaden our existing knowledge of factors associated with longevity in MS. These results will also provide a vital estimate of the impact of immunomodulatory therapy on survival and specific causes of death for MS. The findings from this research will have a profound impact on the care, monitoring and treatment of the disease.

The anti-inflammatory effects of exercise in patients with chronic obstructive pulmonary disease

The number of individuals suffering from chronic obstructive pulmonary disease, or COPD is on the rise in Canada and around the world. COPD, is an inflammatory disease primarily associated with lung inflammation. Inflammation also extends beyond the lungs, and the presence of inflammatory factors in the blood causes blood vessel and heart disease, increasing a COPD patient’s risk of heart attack and stroke. Exercise training is known to have anti-inflammatory effects that are beneficial in the treatment and prevention of a number of chronic conditions. However, the effects of exercise on inflammation in the airways and blood of COPD patients is not well understood. It is also unknown whether exercise training can reverse some of the detrimental effects of inflammation in the blood vessels and brains of patients with COPD and reduce their risk of having a heart attack or stroke. To answer these important questions, Dr. Neil Eves will be conducting two studies. His first study will investigate how exercise training affects the airway and blood inflammation of patients with COPD. His second study will investigate how exercise training improves blood vessel function in patients with COPD and whether these improvements are related to changes in inflammation. Reducing inflammation with exercise in patients with COPD could greatly improve the health of these patients and reduce secondary morbidities associated with the disease.

Balancing immunity and inflammation in the intestine

The human gut is a unique environment, simultaneously tolerating an endless variety of food particles and billions of helpful bacteria while retaining the ability to recognize and respond to potentially dangerous infectious diseases. In the developing world, gut infections such as cholera, amoebic dysentery, and parasitic worms are the leading causes of disease and death and are a major burden on development. Gut inflammation is also involved in inflammatory bowel disease and colorectal cancer. More than 200,000 Canadians suffer from inflammatory bowel disease (one of the world's highest incidence rates) and each year more than 22,000 Canadians will be diagnosed with colorectal cancer.

Dr. Colby Zaph studies mouse models of intestinal infection and inflammation in the gut in order to identify and understand the molecules and cells that regulate the balance between immunity and inflammation. His unique approach is to study the immune responses that develop after the gut is infected with a worm parasite called whipworm (Trichuris), which infects more than 800 million people globally.

Dr. Zaph hopes that his work will aid in understanding how the body knows it is infected (sensing), how it kills the invading organisms (inflammation), and how it turns off the response to stop inflammatory diseases from developing (resolution). The results from his research will hopefully identify pathways and targets that can both promote protective immune responses and eliminate inflammatory diseases of the intestine, including infectious diseases, inflammatory bowel diseases, and colorectal cancer.

Investigating pharmaceutical policies, coverage, and costs

Prescription medicines play a key role in the treatment and prevention of disease, as evidenced by the fact they are the second-largest and fastest-growing component of health care expenditures in British Columbia. Dr. Michael Law's research program includes studies on the broad themes of pharmaceutical policies, coverage, and costs. Pharmaceutical Policies. In January 2009, a policy change in British Columbia gave pharmacists the authority to independently modify and renew prescriptions. While this policy was intended to improve patient access to drugs and reduce the already heavy burden on primary care physicians, concerns have been raised about potential negative effects on patient safety due and reduced continuity of care. This policy has not been rigorously evaluated.

Dr. Law is currently studying the effects of this policy change on drug utilization and costs, patient adherence to medication, and the number of visits patients make to physicians and hospitals. Pharmaceutical Coverage. Canadians pay for prescription drugs through a patchwork of mechanisms, including public drug programs, private drug insurance, and out-of-pocket payments. In 2008, private insurers paid $9.3 billion in drug costs, representing 31% of overall expenditure. Despite this, we have little sense for how private health benefits plans are changing in light of tough economic times. He is currently leading an investigation into private drug insurance benefits in Canada. Pharmaceutical Costs.

Dr. Law is conducting a series of studies on pharmaceutical costs. This research includes a Health Canada-funded study investigating the factors related to cost-related non-adherence to prescription medicines, an investigation into generic drug prices in Canada compared to international peers, and a continuation of his past work studying the influence of direct-to-consumer advertising on prescribing of medicines. Dr. Law’s research promises to help inform the future design and refinement of important and controversial pharmaceutical policies, provide insights into the trends in private drug insurance benefits in Canada, and create greater understanding of the influence of drug pricing on compliance. This research has the potential to create important changes in the health care system.

Mechanisms of impaired functional recovery in diabetic mice following stroke

Diabetics are two to four times more likely than non-diabetics to suffer a stroke during their lifetime, and their prognosis for recovery from stroke is poor. Diabetes is known to negatively affect blood vessels throughout the body, including the eye, heart, kidney, and limbs, leading to a heightened risk of stroke in diabetics. Poor circulation and peripheral nerve damage can lead to blindness, hearing loss, foot injury and amputation. High blood pressure is common in diabetics and increases the risk of heart disease and stroke. However, little is known about how the vascular changes associated with diabetes affect the brain and contribute to poorer recovery of function following stroke.

Dr. Kelly Tennant's research will determine why diabetics suffer from greater impairments following strokes. She will monitor changes in neurons and blood vessels over time following a stroke in diabetic mice and assess the relationship between these changes and recovered use of the forelimb. Dr. Tennant will employ cutting edge in vivo imaging technologies such as intrinsic optical signal, two-photon, and voltage sensitive dye imaging, combined with behavioural testing of forelimb function.

These experiments will shed light on how neurons and blood vessels of diabetics respond differently to ischemic stroke and how these differences contribute to poor behavioural recovery in diabetic stroke survivors. This research will aid understanding of the greater impairment caused by stroke in diabetic patients and lead towards development of treatments that ameliorate the negative effects of diabetes on the brain.