Steroid hormones have profound effects on human physiology and behaviour. They are critical for the nervous system to develop and function normally, and play a role in psychiatric and neurological diseases. The levels of one steroid hormone, DHEA (dehydroepiandrosterone), drop dramatically as people age. DHEA supplements have been promoted in the media as a “fountain of youth” that can reverse brain aging and cognitive decline. However relatively little is known about the actions of DHEA on the nervous sytem and how DHEA acts at the cellular and molecular level. In earlier research, Dr. Soma showed that DHEA increases aggressive behaviour and the size of specific brain regions. Now Dr. Soma is further clarifying the effects of DHEA on behaviour and neuroplasticity (the brain’s natural ability to form new nerve cells and new connections after a change in the environment). He is assessing whether DHEA must be converted to sex steroids such as testosterone and estrogen to affect the brain. The research could improve understanding of the physiological functions of DHEA in humans, and help determine how DHEA treatment could be used to alleviate mental illness and increase neuroplasticity.
Research Pillar: Biomedical
Regulation of the BACE gene expression in the Alzheimer's disease pathogenesis
Alzheimer’s disease is the most common neurodegenerative disorder leading to dementia. The disease affects about 10 percent of people over the age of 65, and prevalence increases with age. Approximately $5.5 billion is spent in Canada each year on people with Alzheimer’s and related dementias. Deposits of the amyloid ß(Aß) protein in the brain are a characteristic feature of Alzheimer’s. Four genes, including APP, have also been linked to the disease. Processing of APP by the BACE enzyme is essential to generate the A-beta protein. In previous research Dr. Weihong Song made important discoveries about the role of presenilin proteins in the development of Alzheimer’s Disease. Now Dr. Song, who holds the distinction of being the youngest physician to graduate in China, is researching the role of BACE in the development of Alzheimer’s Disease. The research could contribute to development of BACE inhibitors, which could improve treatment of Alzheimer’s.
Protein and lipid transport in health and disease: molecular mechanisms of endocytic sorting
Lysosomal storage diseases involve an inherited enzyme deficiency caused by genetic defects. Every cell has hundreds of lysosomes, which contain digestive enzymes used to break down complex cell components such as proteins into simpler components for the cell to reuse. In lysosomal storage diseases fatty substances called sphingolipids accumulate inside brain cells and cause progressive neurological degeneration and early death. Potentially, a lack of digestive enzymes may be the root cause. Recent research also suggests that the way the brain transports cholesterol may contribute to the damage associated with these diseases. The Saccharomyces cerevisiae yeast uses genes that are similar to those found in humans to control the transport of proteins and fats inside the cell. Dr. Elizabeth Conibear is identifying these genes in yeast and in mammalian cells. The research could help reveal ways to change the transport and storage of cholesterol and other lipids, which could lead to methods of preventing accumulation of fatty substances in the brains of children with these diseases. Developing a better understanding of how the cell transports cholesterol could also have important implications for treating adults with heart disease.
Synapse assembly and plasticity
In order to combat neurological disease and mental illness, a greater understanding of how the brain functions at the molecular and cellular level is needed. If we can learn how nerve cells form connections during development, we can develop therapies for regenerating connections following injury. Dr. Ann Marie Craig is leading an effort to understand how nerve cells form and modify synaptic connections. Her group uses a combination of fluorescence imaging, molecular biology, and electrophysiology to investigate how nerve cells communicate. By studying nerve cells growing in a dish, the scientists have already begun to identify molecular signals on the surface of nerve cells that induce contacting partners to form a synaptic connection. Mutations in one of these molecular cues has recently been linked to autism. Dr. Craig and her team are also studying how neurotransmitter receptors are localized and modified to control the strength of synaptic signaling between nerve cells. Given that synapses are the basic units of communication in the brain, the knowledge gained from understanding synapse development and modification has broad implications for the treatment of all neurological diseases and mental illnesses.
Structural studies of clinically-relevant protein-carbohydrate interactions
Thanks to new scientific methods, including use of high-speed computers, the search for ways to diagnose, treat and cure disease has changed greatly in the last 50 years. While chance discoveries are still important, new technology allows researchers to systematically probe the molecular nature of disease-causing organisms and the medicines being developed to treat them. X-ray crystallography is a technique to determine the three-dimensional structure of crystallized molecules. Dr. Stephen Evans is using the technique to study the interactions between proteins (such as antibodies and enzymes) with carbohydrates to learn about the atomic structure of these molecules. In one project Dr. Evans is investigating the antibodies responsible for inherited immunity to learn how the body reacts to new and emerging diseases. In another project he is investigating how a protein molecule can mimic a carbohydrate and be used to vaccinate patients against their own cancer. He is also examining how enzymes can be used to make new carbohydrates that can, in turn, be used as new medicines. Finally, Dr. Evans is developing a new version of his SETOR molecular graphics software that will enable researchers to reduce complicated molecular structures to simplified illustrations.
Molecular Basis of Campylobacter jejuni Infection
Campylobacter jejuni (C. jejuni) is the leading cause of bacterial food poisoning worldwide, infecting approximately 300,000 Canadians, three million Americans, and even higher numbers in developing countries each year. Most cases result from eating contaminated poultry; other causes include exposure to young animals and drinking contaminated water or milk. The bacteria cause severe bloody diarrhea, vomiting and fever, and can lead to more serious medical problems such as bowel disease, arthritis and paralysis. Compared to well-studied bacteria like E. coli and Salmonella, relatively little is known about how C. jejuni causes disease. Using new genetic tools, Dr. Erin Gaynor is identifying and characterizing C. jejuni genes involved in causing infection. She is examining the interaction between the pathogen and host cells to determine how the bacteria cause disease at the molecular level. Dr. Gaynor is also investigating why C. jejuni causes disease in humans when it harmlessly inhabits the intestinal tracts of many other animals, and how host systems respond to infection with the bacteria. This research may lead to a greater understanding of the mechanisms of pathogenesis for C. jejuni and contribute to the development of new treatments and potentially a vaccine to prevent infection from occurring.
An in vivo model of abnormal neuronal circuit formation: the role of glutamatergic synaptic transmission in dendritic arbor growth and synaptogenesis
The causes of many brain diseases, such as epilepsy and schizophrenia, are unknown. Researchers such as Dr. Kurt Haas are exploring the possibilities that abnormal brain development in the prenatal stage may play a role. Using a powerful gene delivery technique, Dr. Haas is investigating how nerve cell activity contributes to brain development, specifically, the effect of altered levels (i.e. too much or too little) of activity on the structure and function of neuronal circuits. This research could lead to more specific and effective interventions to prevent abnormal circuits from forming during prenatal development, and also to treat adults with schizophrenia or epilepsy.
A novel approach to studying DNA copy number variation in schizophrenia and bipolar disorder
Schizophrenia and bipolar disease are severe mental illnesses that affect thinking, mood and behaviour, and cause lifelong disability. Schizophrenia alone costs the Canadian economy about $2.5 billion per year. While the exact causes remain unknown, both disorders are thought to arise from the interaction of genetic defects with environmental factors. Research into these psychotic disorders lags behind advances in other health fields, so new and innovative research strategies are needed. Studies have shown that certain DNA changes can strongly predispose people to psychotic disorders, but the full scope of DNA changes in schizophrenia and bipolar disease has not been explored. Dr. Robert Holt is using new technology called microarray comparative genome hybridization to scan the entire genome of patients with schizophrenia and bipolar disease to detect losses or gains of DNA. The research could contribute to better understanding of the genetic factors that predispose people to schizophrenia and bipolar disorder, lead to diagnostic tests to identify those at risk, and strategies for early intervention to achieve better outcomes.
Shaping the outcome of viral-mediated autoimmune myocarditis
Coxsackievirus infections can cause a variety of illnesses, including heart disease. In North America, the coxsackievirus is estimated to cause up to 30 percent of new cases of dilated cardiomyopathy, a condition in which the heart becomes enlarged and pumps less strongly. Dr. Marc Horwitz is studying how viruses such as coxsackievirus can induce autoimmune diseases such as chronic heart disease, and how immune system components shape and control development of the disease. Studies have shown that the body’s immune response has a profound effect on the development of chronic heart disease after infection with the virus, revealing that immune cells and antibodies that attack infection also damage heart tissues. Dr. Horwitz is examining how innate and adaptive immune responses following viral infection contribute to development of chronic heart disease. He will use findings from the study to design and test new methods to prevent heart disease, which could also lead to new treatments.
The function of ING proteins in S. cerevisiae
Tumour suppressor genes, such as ING1, help regulate normal cell growth by encoding proteins that inhibit abnormal proliferation of cells. Dr. LeAnn Howe is studying the molecular properties and function of ING1 proteins to understand the processes that lead to the development and growth of tumours. Research has linked ING1 proteins to modification of histones, the main protein component of chromatin, which makes up our chromosomes and genes. Evidence suggests that defects in regulation of chromatin structure may improperly activate or silence genes, leading to disease. Dr. Howe is examining the way ING proteins interact with chromatin to determine whether the proteins can modify chromatin. This research could help explain the role of ING1 genes in cancer development and contribute to new cancer therapies.