The sophisticated approaches of genomics are increasingly being used to analyze the majority of the genetic material contained within cells. The tools of genomics have catalyzed remarkable developments in health and disease research. These tools continue to evolve at a rapid pace, making possible additional health research opportunities that are increasingly comprehensive. Dr. Marco Marra is Director of the British Columbia Cancer Agency Genome Sciences Centre. Dr. Marra was funded as an MSFHR Scholar in 2001, with a specific focus of using genomics to comprehensively search for genes that play roles in cancer. In 2003, Dr. Marra also distinguished himself as leading the team that cracked the genetic code for SARS. In addition to his continuing work in cancer genomics, Dr. Marra is also working to identify and analyze DNA mutations correlated with, or causing, mental retardation. A consistent theme in Dr. Marra’s research is the identification and analysis of new genes and new gene products to determine their potential for use as new therapies or vaccines to combat cancer, infectious diseases, and other disorders.
Research Pillar: Biomedical
Applications of bioorganic chemistry to medicine
Chemistry plays a central role in uncovering the mysteries of biology, and in the generation of new ways to approach diagnostics and disease therapies. An exciting area for health research is in the development of synthetic chemistry – the creation of “man made” molecules that contain properties that regular DNA does not possess. This merging of chemistry and biology towards medically relevant goals—such as developing antiviral compounds or radiopharmaceuticals for diagnostics or treatment—represent a powerful combination. Dr. David Perrin’s work involves the creation of synthetic DNA and peptides that may be useful in recognizing, imaging and ultimately interfering with or halting disease processes. He generates new molecules based on amino acids and nucleic acids, which have potential for disrupting RNA activity in diseases such as cancer or HIV. In addition to researching the use of synthetic DNA in disease therapies, Dr. Perrin has developed a new class of PET imaging (Positron Emission Topography) probes for the efficient radiolabelling of biomolecules. These biomolecules have the potential to image and possibly eradicate cancer directly or permit more precise monitoring of its progression in conjunction with other targeted therapies.
The role of RNA in the evolution of life
One of the fundamental issues facing biology is the question of our origins. Despite the fact that time and evolution have erased much information about early life on earth, a number of fascinating clues remain within cells that have led to the proposal of an “RNA world” hypothesis – the premise that RNA (ribonucleic acid) was once the dominant biological catalyst, capable of important metabolic functions that are currently performed by protein enzymes. Dr. Peter Unrau is exploring the chemical versatility and evolutionary potential of RNA. He has been examining the ability of RNA to replicate independent of protein. Along with his chemical interests in RNA, he is also exploring the processing of RNA by eukaryotes (cells with a distinct membrane-bound nucleus) and studying the interaction of small RNA processing and viral replication in plants and humans.
Targeting the beta cell for Diabetes therapy
In healthy people, blood glucose levels are tightly controlled by insulin, a hormone produced by beta cells in the pancreas. When the blood glucose elevates (for example, after eating food), insulin is released from the pancreas to lower the glucose level. In type 1 diabetes, beta cells are destroyed by one’s own immune system. In type 2 diabetes, insulin secretion from beta cells is insufficient and beta cells are gradually lost due to the toxic effects of fats, high glucose levels and build-up of toxic amyloid deposits in the pancreas. Dr. Verchere’s research is focused on understanding how beta cells normally function in health, and what goes wrong in diabetes. He is investigating why toxic islet amyloid deposits form and how they kill beta cells, as well as how immune cells kill beta cells in type 1 diabetes. He is also looking at ways to protect transplanted beta cells from immune destruction. His long-term goal is to develop novel therapies that enhance beta cell survival and function in type 1 and type 2 diabetes.
Source, Target and Biological Role of 14-3-3 Proteins in Rheumatoid Arthritis
Rheumatoid arthritis (RA) is the most common autoimmune disease worldwide and affects ~1% of Canadians. Its chronic inflammation causes pain and joint failure, eventually leading to disfiguration and disability. The cartilage and bone destruction of RA is thought to be caused by a certain family of enzymes, MMPs, that are capable of breaking down all joint components, causing severe damage and pain. Recently, 14-3-3 proteins were discovered to be critical communication proteins between skin cells during the healing process. 14-3-3 proteins also stimulate production of MMPs. Thus, the abnormally high amounts of 14-3-3 found in RA joints might be responsible for excess MMPs production, which leads to joint destruction. Jennifer is studying how 14-3-3 proteins may stimulate production of MMPs and lead to the joint destruction in RA. Ultimately, her work will contribute to the development of novel therapeutic strategies to diagnose and treat RA and other arthritic diseases.
The role of p53, p63 and p73 in the survival of oligodendrocytes following spinal cord injury
Spinal cord injury can be characterized into two broad pathological events known as the primary injury, typically a blunt force trauma, and the secondary injury, an ensuing degradation of both neurons and glial cells. The secondary injury is characterized by vascular alterations, poor blood flow, production of free radicals, oxidative stress, ionic imbalance, inflammation and excitotoxicity, which has a very large impact of the survival of oligodendrocytes, the cells responsible for myelination in central nervous system. These event occur days to weeks following the injury making them suitable for pharmacological intervention. Recent work has implicated p53 and p63 as pro-apoptotic (programed cell death) and p73 as antiapoptotic for neurons. Using animals which are absent of these factors specifically in oligodendrocytes, I wish to examine their affect on the survival and apoptosis of oligodendrocyte following a spinal cord injury. I also wish to correlate this difference in oligodendrocyte survival and apoptosis to the behavioural outcome of these animals. This will enable the validation of p53, p63, and p73 as targets to promote survival of oligodedrocytes following spinal cord injury. lf that is the case, it would suggest the need to develop novel treatments that target these proteins for potenetial future clinical application.
Prenatal Alcohol Exposure: Fetal programming, stress responsiveness, and vulnerability to depression and addiction
Women who consume large quantities of alcohol during their pregnancy can deliver babies with Fetal Alcohol Syndrome (FAS) or Alcohol Related Neurodevelopmental Disorder (ARND). Adults with FAS/ARND can exhibit a range of motor, behavioural and neurodevelopmental deficits. They also have higher rates of addiction and depression compared to the normal population. However, the relationship between prenatal exposure to alcohol and these psychiatric conditions is not known. One consequence of prenatal alcohol exposure (PAE) is re-programming of the neural system involved in stress, known as the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA axis during stressful situations is, in the short term, an adaptive response. But prolonged activation or an inability to “shut off” this system can have drastic consequences on brain function and behaviour. HPA dysfunction is implicated in the cause of depression, and activation of this system through stress can influence the initiation and maintenance of, as well as relapse to, drug addiction. Kim Hellemans is exploring how changes in the neural wiring of the HPA through PAE influences behaviours and neuroendocrine function associated with addiction and depression. Early targeting and prevention of psychiatric conditions is a critical goal of health research; the aim of Kim’s research is to determine whether normalizing HPA dysfunction in children with FAS/ARND can prevent their vulnerability to depression and addiction in adulthood.
Nuclear liver X receptors in the pathogenesis of, and the innate immunity against Samonella enterica
Salmonella enterica infections represent a serious public health problem. This bacterium causes diseases ranging from typhoid fever to food poisoning, affecting millions of people each year. Currently, there is little understanding of how Salmonella causes disease and the role of the immune system during the infection. The innate immune system is the first line of defense against pathogens, and is considered to be very important in defining the outcome of Salmonella infection. Recent evidences suggest that important components of the innate immune responses are modulated by some of the same elements involved in the control of various metabolic pathways. Previously, Alfredo Menendez was funded by MSFHR for his PhD research into the generation of a prophylactic vaccine against HIV-1. Now, Alfredo is studying the innate immune response against Salmonella, and the interplay between the control of inflammation and metabolism in the setting of Salmonella typhimurium infection, in vitro and in vivo. Research in this field may lead to the development of improved or novel treatments or vaccines for Salmonella through the enhancement of the innate immune response
Roles of the cilium, a sensory organelle, in health and disease
Cilia are slender appendages that protrude from most cells and tissues in humans. The motile forms produce whip-like motions, while the non-motile (known as “primary”) forms act as antennae, detecting chemical and physical changes in their environment. Both forms of cilia are critical to human health. For example, motile cilia propel sperm in males, and move debris in respiratory airways. Primary cilia are implicated in sensory processes such as vision, sense of smell and hearing. Defects in the forms or functions of cilia can cause a wide range of human ailments, including kidney and heart disease, obesity and diabetes, and sensory impairments such as blindness. Using bioinformatics, genetics, cell biology, biochemistry and genomics approaches, Dr. Michel Leroux is studying previously unknown components of cilia and characterizing them in the nematode C. Elegans and in human tissue culture cells. He is also working to identifying genes associated with the many ciliary disorders in humans, including some associated with obesity and cystic kidney disorders. By providing fundamental insights into the form and functions of cilia, Dr. Leroux’s studies may uncover new potential targets for therapy in a wide range of human diseases.
Sensory function and dysfunction in neurotrauma: models, molecules and mechanisms
Spinal cord injury (SCI) interrupts the flow of information between the brain and spinal cord. As a result, people with SCI experience muscle paralysis. They also experience changes in sensation, ranging from a complete loss of sensation to chronic pain. Dr. Matt Ramer’s research focuses on the sensory nervous system and how its changes due to trauma related to sensory dysfunction. In particular, he is interested in the balance between factors that promote or inhibit the growth of nerve fibres (axons). Dr. Ramer is investigating the effects of growth-promoting and growth-inhibiting molecules on the anatomy of spinal sensory axons, on their connectivity within and outside the spinal cord, and on behavioural outcomes resulting from spinal cord injury. This work will increase our understanding of sensory dysfunction and may identify new therapies for SCI.