Melanoma gene therapy by conditional replicative adenovirus targeting PUMA and p-Akt

Melanoma is a deadly form of skin cancer arising from the abnormal growth of pigment-producing cells in the skin. Melanoma is an aggressive tumour that spreads quickly to other parts of the body and is very difficult to treat because it does not respond to radiation or chemotherapy. In recent years, researchers have turned to gene therapy as a new approach to fight cancer. This approach is based on the idea that cancer is caused by defective genes. The goal is to eliminate the cancer by inserting therapeutic genes into cancer cells using a vector (a vehicle for delivering genetic material to a cell). Within melanoma cells, the expression (activation) of the cell death gene PUMA is often reduced and expression of the cell growth and survival gene Akt3 is often inappropriately increased. Using viral vectors known as CRAds, Alison Karst is focusing on reversing this pattern of gene expression in order to induce melanoma cell death. CRAD-based gene therapy holds promise for eliminating cancer cells and more effectively treating melanoma.

Cell fate mapping of putative neural stem cells

Disease states such as Alzheimer’s, Parkinson’s, stroke and spinal cord injury each affect the nervous system in what was once thought to be an irreversible manner. However, recent scientific evidence suggests that damaged areas of the nervous system may have their functions restored by transplantation of neural stem cells or by administration of molecules that coax the body’s neural stem cells to self-repair. To put this knowledge into practice, researchers require a better understanding of the basic mechanisms of stem cell development. Barbara Murdoch was previously funded by MSFHR to identify proteins specific to the surface of neural stem cells so she can study their growth requirements. Building on this, she is now using olfactory epithelium cells to determine the role of the protein nestin in the development of neural stem cells. She is studying which cell types express (produce) nestin and determining their pattern of expression. By understanding these mechanisms, she hopes to contribute key knowledge necessary for effective clinical applications requiring stem cell transplantation, expansion and gene or drug therapies.

Effect of cholesterol on prohormone processing in pancreatic beta cells in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is a devastating chronic disease affecting close to two million Canadians. The disease is characterized by a loss of insulin action in tissues such as muscle and a loss of insulin secretion by the islet beta cells of the pancreas. The number of beta cells within the pancreas – an important determinant of the amount of insulin secreted – is decreased in persons with type 2 diabetes. This supports the idea that the progressive loss of insulin secretion in this disease is due to a loss of functional beta cells. The loss of beta cells is associated with the formation of toxic islet amyloid deposits, consisting primarily of the beta cell peptide islet amyloid polypeptide (IAPP or amylin). Although the mechanism underlying islet amyloid formation is not known, impaired processing of the IAPP precursor, proIAPP, has been proposed to be an important initiating event. In type 2 diabetes, elevated glucose and free fatty acids can cause beta cell dysfunction, which raises the question whether elevated cholesterol induces beta cell dysfunction in this disease. Zainisha Vasanji’s research is aimed at determining whether exposure of beta cells to elevated cholesterol is the trigger for the chain of events that lead to islet amyloid formation in type 2 diabetes. Zainisha’s study may help delineate the cause of the beta cell defect in type 2 diabetes and may lead to new therapies to prevent the progressive loss of insulin secretion in this disease.

Characterization of the influence of covalent histone modifications on DNA methylation in mammalian cells using a novel genomic targeting system

Normally, cells in the body grow, divide, and die in an orderly manner, under the direction of their DNA, the genetic blueprint of life. However, damage to the DNA in a single cell can disrupt this regulated process, prompting the cell to begin dividing uncontrollably and becoming cancerous. A subset of cell growth regulating proteins – those encoded by the tumour suppressor genes – normally act to inhibit cell growth. In many cancer cells, these proteins are no longer produced, not because the genes that encode them have become mutated, but because they have been shut off, or “silenced”. Gene silencing frequently involves methylation, a specific chemical change in the genes’ DNA. However, the cause of methylation and its associated gene silencing cascades remain unclear. Dr. Lorincz is determining the underlying cause of DNA methylation, using a novel mouse cell model system that he has developed. The knowledge gained from this work may lead to the development of pharmaceuticals that inhibit DNA methylation and, in turn, provide new agents for the treatment of those cancers arising from aberrant methylation of tumour suppressor genes.

Selective attention systems and their integration in children with Autism

Autism — a neurological disorder characterized by impaired communication and social interaction — is a severe and pervasive developmental disorder that usually appears in the first three years of a child’s life. Children and adults with autism have varying levels of difficulty with social interaction and communication. Early predictors of autism include the inability to notice and make meaning of social cues such as eyes and faces, while displaying an intense focus and attention to seemingly irrelevant, non-social objects such as watches or cars. These attentional disturbances are thought to play a key role in the development of perceptual abnormalitities, hindering social and emotional competence.

Dr. Grace Iarocci is investigating attentional disturbances in children with autism, Employing a series of computer tasks, she is assessing how the children’s orientation and selection attention processes are coordinated and integrated across vision and hearing. This innovative approach focuses on providing comprehensive and precise assessments of the efficiency of each of the processes of attention, as well as insight into the complexity of the organization and function of theses processes.

Dr. Iarocci is using the information gathered from this research to develop interventions that tackle the early markers underlying the behavioural symptoms of autism.

Social class and health: Innovative theoretical exploration and empirical confirmation

Two broadly-defined approaches to conceptualizing social class can be applied to the empirical study of health inequalities. In the first, social class is equated with the socioeconomic status of individuals, i.e., with individual-level measures of wealth, educational credentials and/or occupational prestige. Explanations for empirical relationships between health and this particular conception of social class generally address material, behavioural or psychosocial phenomena, such as housing conditions, lifestyle choices or perceptions of relative standing. In the second, social classes are social groups, defined by the nature of their relationships to the economic mode of production and forms of control wielded in the workplace (the perspective of the neo-Marxist theorist Erik Olin Wright), or defined relationally in social space by their possession and utilization of various economic, educational, social and cultural capitals (the perspective of the French social theorist Pierre Bourdieu). In this tradition, explanations for class-health associations attempt to simultaneously address individual-level and group-level factors in a complex mix of agency and structure. Dr. Gerry Veenstra is investigating relationships between social class and health and well-being in Canada, integrating individual-level models founded upon material, lifestyle and psychosocial explanatory factors with social-structural theoretical frameworks inspired by theorists like Bourdieu and Wright. Building upon his previous work in BC, Dr. Veenstra will engage in an ethnographic exploration of different class positions and then administer a questionnaire survey to randomly-selected Canadian adults, assessing possession of various manifestations of control and capital. He will apply linear-causal statistical techniques such as regression analysis and relational techniques such as multiple correspondence analysis to this survey data in an attempt to identify and explain factors underlying social class and health inequalities in Canada.

The Operations Research Team in Cancer Care

This award supports the development of a multidisciplinary research team focused on applying operations research methods to improve access to cancer treatments. Initially the team will focus on access to radiation therapy, which is used by half of all cancer patients. The team’s objectives will be to develop operations research models that enhance access to radiation therapy and improve clinical outcomes; test and validate the models; and apply the research to improve access to cancer treatments in general.

The role of perfectionism, stress, and interpersonal discord in chronic headache disorders: A daily process study

Headache disorders are a prevalent health issue affecting between 10 to 35 per cent of the Canadian population. Headache disorders—which range from migraines to tension headaches—are associated with significant emotional, social and economic costs, including lost work days, decreased productivity and increased health care costs. There is increasing interest in understanding the role of psychosocial influences, such as personality traits, interpersonal interactions, coping and stress, in the onset, frequency and severity of headaches among sufferers. Perfectionism is a personality trait that has been identified as a potential risk factor for headache disorders. Perfectionists tend to experience greater stress due to their high expectations, self-critical tendencies and interpersonal conflict. Dayna Lee-Baggley is examining how perfectionism may generate and magnify risk factors (e.g., stress) for headache episodes. Her study is the first to monitor perfectionists’ experience of headaches on a daily basis. By identifying the risk factors associated with headache disorders, Dayna’s research will allow researchers to identify targets for intervention that could prevent or minimize the occurrence and impact of headaches for a substantial group of people.

Genetic determinants of the host response to infection in critically ill adults with systemic inflammatory response syndrome

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.

The relationship between emotion processes and health in children at-risk for the development of anxiety disorders

While feeling shy, uncertain, or apprehensive with strangers or in new situations is common in young children, an excessive display of these behaviours can negatively affect day-to-day functioning. Disruptions in friendships and social activities, decreased school attendance and performance, and increased family conflict are all common consequences of extreme shyness. Research shows that children who consistently respond in these ways are more likely to develop anxiety disorders later in childhood and adolescence. Furthermore, older children and adults who display this pattern of behaviour have more general health complaints and problems. Sherri Frohlick is conducting a study aimed at understanding the development of these general health complaints by examining the ability of preschool-aged shy children to understand and express different emotions, and determining the effect of this on their health status. Just as being able to identify and communicate different emotions is an important part of healthy psychological growth, not having these skills is linked to emotional and behavioral problems such as depression, anxiety, aggression or other serious forms of psychological dysfunction. By examining emotion identification and communication as processes underlying health complaints and problems in young children, Sherri is working to develop prevention and intervention programs that identify their needs more directly and lessen health concerns. A reduction in health complaints would lessen the burden on a health care system faced with the challenge of diagnosing and treating these problems.