Modulation of ocular motor decisions by reward: an investigation of neural processes using converging methods

The prospect of reward or punishment is known to affect how people make decisions. However, it is not clear which neural systems are involved in this process. This is an important topic in healthcare, because impaired processing of reward information is known to affect the decision-making abilities of many people, including those with damage to the frontal lobe of their brains, Parkinson’s disease, depression/anxiety, obsessive compulsive disorder, and even normal aging. A striking example of this situation occurs among some people with Parkinson’s disease, who can develop pathological gambling behaviours as a result of taking dopaminergic drugs. An effective way to study these neural systems is to track eye movement decisions – in other words where people focus their visual attention. Typically, people are faster to make an eye movement and are more accurate in their eye positions when the movement is rewarded by monetary gain. However, these effects are degraded in certain psychiatric conditions, such as anxiety and depression. Dr. Linda Lanyon is investigating the brain circuits that mediate these reward-related decisions in healthy humans. Her findings will enable her to develop a computer model of the brain circuitry and function that is able to simulate the behaviours observed in humans. In addition to demonstrating how these systems operate in healthy humans, the computer model can also be selectively damaged in order to simulate pathological behaviours observed in patients. By using healthy subjects to create a computer model for decision-making, Linda hopes to improve the understanding of the pathology of neurologically-impaired circuits.

Regulation of the BACE1 gene expression in Alzheimer's Disease pathogenesis

Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia, affecting approximately 10 per cent of the Canadian population over the age of 65. One of the pathological hallmarks of AD is increased deposition of the beta-amyloid protein, which forms amyloid plaques in the brains of AD patients. This is caused by dysfunction of the BACE enzyme, which regulates processing of the amyloid precursor protein to generate beta-amyloid proteins. Levels of the BACE enzyme have been shown to be elevated in Alzheimer’s. Philip Ly is interested in studying the underlying molecular mechanisms regulating the BACE enzyme expression and activity. He is studying a region of the BACE gene called the BACE promoter. This region has been demonstrated to be important for BACE expression. However, the regulations at the level of BACE gene transcription – the first step in the expression of the genetic information – remain elusive. Using a series of molecular and biochemical approaches, Ly is examining the transcriptional controls that regulate BACE gene expression in neurons. He is also examining if specific mutations in these transcription factors affect BACE expression and contribute to AD pathogenesis. Ly’s research will be the first to thoroughly characterize the transcriptional regulation of the BACE1 and the role of abnormal gene expression in AD pathogenesis. In addition to providing much needed information regarding signal transduction in amyloid precursor protein processing, these studies have important pharmaceutical implications, such as potential development of BACE enzyme inhibitors to improve treatment of Alzheimer’s disease.

The role of SHIP's C2 and PH domains in regulating hematopoietic cell growth and function

Various cancers and inflammatory diseases occur as a result of inappropriate activation of the body’s blood-forming hematopoietic cells. Normally, cellular activation, growth and survival in hematopoietic cells are regulated by the phosphoinositide 3-kinase (PI3K) pathway, which drives a wide range of cellular processes. Keeping tight control on this pathway is SHIP (SH2 domain-containing inositol 5′ phosphatase), a counteracting enzyme that inhibits PI3K action. SHIP is found only in blood and immune system cells and is the major restraining mechanism in these cell types. Loss or impaired activity of SHIP – in effect, removing the brakes on the PI3K pathway – has been implicated in certain leukemias and in inflammatory disease. Recently, researchers discovered small molecules that are capable of enhancing SHIP activity, resulting in both the inhibition of immune cell activation and the death of hematopoietic cancer cells. This represents a previously unknown mode of regulating SHIP enzyme activity. Andrew Ming-Lum is determining the significance of this novel type of regulation of SHIP function. Using cell lines and mouse models, he is focusing on a previously unrecognized domain on the enzyme, upon which the small molecules are believed to act. These studies will provide greater insight into how this mechanism affects the function, growth and survival of hematopoietic cells. It will also provide insight into the dysregulation that occurs in certain cancers and inflammatory diseases.

Translational TB Research: Identification of Novel Drug Targets and Development of Protective Vaccines

A recent report from the World Health Organization revealed that about 1.5 million people died from TB in 2006. In addition, another 200,000 people with HIV died from HIV-associated TB. Current strategies aim to reduce the annual death toll from TB to less than 1 million worldwide by 2015, as set out in the United Nations Millennium Development Goals. Infection by the Mycobacterium tuberculosis microorganism causes TB. The current global strategy for TB control is based on reducing the spread of infection through massive vaccination campaigns with the BCG (bacille Calmette-Guérin) vaccine, and treatment of individuals with active disease using multi-drug combinations. However, there are challenges to this approach, including inefficiency of the BCG vaccine, the emergence of drug resistant strains of Mycobacterium tuberculosis (Mtb) and the difficulty in delivering a treatment that requires multiple drugs over periods of six months or more.

Until recently, little was known about how Mtb alters the host immune system to cause infection. Through Dr. Zakaria Hmama’s work as an MSFHR Scholar over the past six years, important new knowledge has been developed regarding the sub-cellular and molecular mechanisms of host/pathogen interactions. His research over the next five years will focus on gene manipulation technologies to upgrade the current BCG vaccine with recent immunological concepts to maximize its protective properties. Hmama is also investigating an important virulence factor identified by his lab as a potential drug target for TB treatment.

Protein tyrosine phosphatase A (PtpA) dependent mycobacterial manipulation of host response to infection

Tuberculosis (TB) is currently the world’s leading cause of mortality due to a single infectious agent. It has been estimated that approximately one-third of the world’s population is infected with Mycobacterium tuberculosis, the bacteria that causes TB. Approximately two million people die of TB annually, and about eight million new cases arise each year. In addition to the emergence of multi-drug resistant strains of the disease, TB develops much more readily in people with HIV infection, and is a leading cause of AIDS-related death. There is an urgent need for novel therapeutics and drug targets in order to control the global spread of TB. In order to evade attack by the host immune system, M. tuberculosis secretes a protein called Protein tyrosine phosphatase A (PtpA). PtpA interacts with multiple proteins in the host that are normally essential for the destruction of bacterial pathogens. However, the exact role of these interactions in relation to the survival of M. tuberculosis within cells is not yet completely understood. Dennis Wong is defining the role of TB-Host interactions and identifying the molecular events that are disrupted by PtpA to promote TB infection. Understanding the mechanisms by which PtpA promotes the survival of M. tuberculosis will provide important insights regarding the pathogenesis of TB and the response of the host immune system to infections. As PtpA is a potential drug target, the new knowledge may contribute to the development of novel therapeutics against one of the deadliest diseases in the world.

Translating gene expression into clinical care for sarcomas and breast cancer

Cancer is one of the leading causes of death in Canada. As a pathologist, Dr. Torsten Nielsen’s job is to accurately diagnose cancer and determine its type from more than 200 possibilities. For more than 50 years, these diagnoses have been made using a light microscope to examine tissue biopsies. However, this can be subjective, requiring the pathologist to make a judgment call in certain cases. Recent new technologies help determine the genetic profile of each type of cancer. This profile can be used to distinguish between cancers that otherwise appear almost identical under the microscope. The ability to detect subtle differences among cancers can be enormously important because the exact diagnosis determines what combination of surgery, radiation, hormone treatment or chemotherapy is the best treatment plan.

Using advanced genetic tools, Dr. Nielsen aims to develop clinical tests that more accurately identify difficult subtypes of cancer, and to then determine which treatments will work best for each subtype. Previously supported by an MSFHR Scholar award, he works with two cancer types in particular: breast cancer and sarcomas (tumours of muscle and bone). With breast cancer, he is working to develop inexpensive and easy-to-conduct clinical tests that accurately diagnose four types not easily distinguished under the microscope. With sarcomas, he is using new molecular tools to develop diagnostic tests and treatments that target specific molecular changes, to see if new drugs can cure these cancers with minimal side effects. His research could lead to simple, effective, and widely available diagnostic tools and personalized treatment strategies that will improve survival for cancer patients.

T regulatory cells and T helper 17 cells: interactions between two distinct T cell subsets important for immune homeostasis

The immune system tries to maintain an optimal balance between immune responses to control infection and tumour growth, and reciprocal responses that prevent inflammation and autoimmune diseases. Impaired immune responses, such as those that occur with autoimmune disorders (multiple sclerosis, type 1 diabetes) and organ transplant rejection, result when a person’s immune system mistakenly attacks normal cells. Currently, patients afflicted with this condition must follow a strict regime of immunosuppressive drugs for the rest of their lives. However, these treatments seriously compromise the body’s ability to fight infection and also increase the risk of developing cancer. Sarah Crome is studying the role of a newly discovered class of cells, called T regulatory (Treg) cells in immune system response. She is studying how Treg cells suppress other immune cells and essentially act as a “brake” for the immune system. She is also examining how a subset of T cells, called T helper 17 cells, cause harmful immune responses that result in the rejection of transplanted tissues. A better understanding of these cells and the interactions and factors that regulate their differentiation and function, may lead to more effective treatments for organ transplantation and autoimmune diseases without compromising normal immune function.

Defining the role of FOXP3 in human CD4+ T cells

In recent years, new immunosuppressive drugs have made considerable improvements to the success of transplantation procedure and the treatment of autoimmune diseases. Despite these successes, the side effects of long-term drug treatment invariably decrease patients’ quality of life and cause generalized suppression of the immune system. To develop a more direct approach for these therapies, efforts are now focused on a particular aspect of the immune system that controls the response. T regulatory (Tr) cells are a subset of white blood cells that have the ability to suppress undesired immune responses, while leaving other aspects of the normal immune system intact. A gene named FoxP3 has been identified as the master controller for development of a subset of Tr cells that can provide protection against some types of autoimmune diseases and promote acceptance of foreign tissue in a transplant setting. FoxP3 plays an essential role in maintaining normal immune function, but the exact mechanisms by which this gene operates in Tr cells are not known. Due to the high potential for using Tr cells for immunomodulatory therapies, Sarah Allan is investigating the role of FoxP3 in human cells. Her research will increase our understanding of how Tr cells arise naturally, the mechanisms by which they suppress immune responses and how they differ from other types of T cells at the molecular and genetic level. This work will contribute to the development of novel therapies for autoimmune diseases, transplantation, and other pathologies of the immune system.

Neuropsychological predictors of medication adherence and employment status following kidney transplantation

For her Master’s research, supported by a 2005 MSFHR Trainee Award, Shannon Gelb researched whether cognitive difficulties (brain functions such as memory and reasoning) exist following a kidney transplant. The research revealed that adult recipients of kidney transplants tend to perform worse than healthy individuals without transplants in tests of verbal memory (the ability to recall verbal information after a delay period) and executive functioning (activities such as multi-tasking and problem-solving). However, the impact of these results on daily life is unclear. Building on this research, Gelb is examining the relationship between cognition and two functional outcomes for kidney transplant recipients: adhering to prescribed medications and maintaining employment. Not taking medication properly, which is associated with increased risk of the body rejecting the transplanted kidney, is a significant problem among kidney transplant recipients. Employment rates among kidney transplant recipients are also poor – 59 to 83 per cent of kidney transplant recipients never return to work following kidney transplantation. The research may help clarify the potential need for increased education and patient support following kidney transplantation.

Health Innovation Design and Evaluation (HeIDE)

In the last decade, the Canadian government has invested billions of dollars in development of a Canadian health information infrastructure. Health information technology goals are varied but they usually include faster, more efficient delivery of care based on shared information through electronic health records. However, despite the investment to develop an information technology infrastructure, the potential gains for the health system have been slow to materialize. Dr. Ellen Balka’s research focuses on the challenges associated with realizing Canada’s vision of an information technology-rich health care sector. She is working with stakeholders in actual health care settings, including technology developers, health system decision makers and health care providers, to assess design shortcomings, usability, implementation challenges, and issues related to governance of information technology within organizations. Dr. Balka’s studies will contribute to a more comprehensive understanding of how complex it is to introduce new information-based technologies into the health sector, and will lead to development of strategies that improve the rate of success for these initiatives within the health system. This will ensure that the potential benefits of these systems and technologies (administrative efficiencies, improved patient care and development of health data for research purposes) can be achieved.