Canada has a growing diabetes epidemic, which costs the Canadian health care system an estimated $13 billion annually. More than two million Canadians have the disease, and by 2010, the number is expected to increase to three million. Diabetes is also a major health problem worldwide. Although diabetes can be treated with insulin, a cure for this devastating disease remains elusive. All forms of diabetes are associated with the loss of functional pancreatic islet cells. However, very little is known about the underlying factors controlling how and why pancreatic islet cells die. Dr. James Johnson recently discovered important networks of molecules that control survival of islet cells. For example, one such network includes the RyR2 protein, which controls the release of calcium in the cell, and the calpain protein, which can split other proteins in response to increased calcium. Dr. Johnson is comparing the role of this survival network to other molecular networks to investigate how pancreatic islet cells die. The research could lead to better therapies for diabetes, including more successful pancreatic islet transplantation, a promising experimental treatment that depends critically on the continued survival of the donated cells. The findings could also improve understanding of other diseases where calcium is involved in cell death, such as heart failure, Alzheimer’s disease and stroke.
Research Pillar: Biomedical
Studies on rational treatment of Parkinson's disease
Parkinson’s disease is a chronic, progressive disorder that affects about 100,000 Canadians, at an annual cost of more than $2.5 billion. The disease involves loss of both brain cells and chemicals that modulate communications between brain cells – causing not only motor symptoms of tremor, stiffness, and slow movements but also cognitive and behavioural changes. Conventional drug therapy for Parkinson’s disease replaces dopamine in the brain. Although most motor deficits usually improve after therapy, more than 50 percent of patients (particularly those in the later stages of the disease) may develop difficult problems, such as involuntary movements, dementia and psychosis. Dr. Chong Lee is studying neural mechanisms of these complications, which are resulting from the disease itself or the chronic use of Parkinson’s drugs. Dr. Lee is also evaluating the effectiveness of neuro-protective treatment, a strategy to prolong the survival of injured cells and slow the progression of Parkinson’s disease. He ultimately aims to develop strategies to treat dementia and behavioural symptoms of the disease and to reduce or prevent treatment-induced complications in patients with Parkinson’s disease.
The role of insect immune peptides in limiting disease transmission by vectors
Vector-borne diseases – diseases spread to humans by insect vectors – pose serious health problems worldwide. Malaria, transmitted by mosquitoes, kills 2-3 million people a year; Lymphatiic filariasis, transmitted by mosquitoes, afflicts more than 100 million people; African sleeping sickness, spread by tsetse flies, affects up to 500,000 people each year, most of whom die within two years of infection; Chagas Disease, transmitted by kissing bugs, is found only in the Americas and affects 30 million people and results in premature heart attacks. In North America, West Nile virus, spread by mosquitoes, has expanded to most regions. Insects have a potent immune system that kills most pathogens (disease-causing organisms). A major component of their immune response is the production of small proteins that kill many bacteria, viruses and parasites. Dr. Carl Lowenberger is studying these immune peptides to identify ways to reduce disease transmission to humans, and to determine if these antimicrobial peptides could be used to treat human infections. Many pathogens have developed resistance to antibiotics. Immune peptides isolated from insects in this research could provide a new source of antibiotics to overcome drug resistance.
Contribution of the ubiquitin/proteasome pathway to coxsackievirus-mediated myocarditis
Myocarditis, an inflammatory heart disease caused by the coxsackievirus, can lead to a dilated (enlarged) heart, which can result in sudden heart failure. A heart transplant is the only treatment for this condition. The proteasome is a cellular garbage collector that accumulates and destroys unwanted or damaged proteins. Ubiquitin is a molecule that latches onto damaged or mutated proteins and flags them for destruction by proteasomes. In earlier research, Dr. Honglin Luo showed that blocking the ubiquitin/proteasome pathway prevents the coxsackievirus from producing proteins, which may affect the ability of the virus to replicate. Now Dr. Luo is further investigating the effect of the ubiquitin-proteasome pathway on replication of the coxsackievirus and development of myocarditis. The research could confirm that inhibiting the pathway limits virus replication and prevents abnormal protein degradation, which could lead to new treatments for myocarditis that reduce progression of the disease to heart failure.
Role of the budding yeast kinetochore in chromosome segregation and checkpoint response
Cells must accurately duplicate their chromosomes (genes in the cell’s nucleus) and segregate them equally to daughter cells for proper cell growth and division. Errors in segregation results in cells with abnormal numbers of chromosomes (aneuploidy), which can lead to birth defects, Down’s syndrome and cancer. Cells have developed safeguards to ensure chromosomes are accurately segregated. A region of each chromosome called the centromere is bound by kinetochore proteins which attach to spindle microtubules, tiny fibres that pull newly separated chromosomes to each side of a dividing cell. If any mistakes occur in spindle attachment, kinetochore proteins signal the spindle checkpoint machinery, which delays segregation until the defects are corrected. Using yeast as a model, Dr. Vivien Measday is studying how kinetochore proteins attach to spindle microtubles and communicate with the checkpoint machinery. The research will improve understanding of chromosome segregation and could lead to treatments for diseases caused by abnormal numbers of chromosomes.
Identification of circulating cells with a myogenic potential
Degenerative diseases have an enormous economic and social impact on BC’s aging population. In the long term, identifying cells that could regenerate organs damaged by degenerative diseases could revolutionize how these conditions are managed. Care could shift from expensive, lifelong drug treatments to therapies that permanently restore organ function. Research suggests that bone marrow contains stem cells (precursor cells that have the ability to develop into cells specific to types of tissues) capable of repairing damaged tissues in adults. To efficiently use stem cells, however, the cells responsible for tissue repair must be identified from among the many cell types present in bone marrow. Dr. Fabio Rossi is identifying bone marrow cells that repair damaged muscle, exploring their characteristics and investigating how they repair damaged tissue. Findings could lead to therapies that efficiently restore organ function.
Intestinal innate immunity: recognition and response to enteric bacterial pathogens
Bacterial infections of the gastrointestinal tract are very common, particularly among children. These infections cause diarrheal outbreaks and millions of deaths worldwide. Bacteria are also a major problem in Canada, with BC having one of the highest rates of intestinal bacterial infection in the country. Bacteria are believed to trigger a variety of gastrointestinal diseases, including inflammatory bowel disease, a debilitating and chronic condition that affects one in every 1,000 Canadians. Despite the prevalence of bacterial pathogens (disease-causing organisms), little is known about how the immune system recognizes and combats intestinal bacterial infections. This information is important because the immune response to these bacteria determines who is susceptible to infection, as well as the severity of the resulting disease. Dr. Bruce Vallance is researching how bacteria cause intestinal disease and how the immune system identifies and fights these infections. Dr. Vallance is investigating whether genetic differences in hosts influence susceptibility to food and water-borne bacteria. He aims to identify immune responses and genetic factors that either protects against intestinal bacteria or causes susceptibility to infection. This research could help explain how bacteria cause intestinal disease and ultimately lead to new treatments to prevent both bacterial infections and bacterial-induced gastrointestinal diseases.
Bioinformatics for the study of gene regulation
Genetic diseases can result from subtle variations in the DNA sequences of genes. Approximately three million differences exist between the DNA of any two individuals. While most of these differences have no functional impact, researchers have linked numerous variations to diseases. These linkages have provided insight into disease development, enabled the creation of diagnostic tests and accelerated the creation of therapeutics. Most of the known functional DNA variations result in decreased activity of proteins produced by a gene. But Dr. Wyeth Wasserman suspects many functional variations actually alter gene activity, rather than the sequence of proteins encoded by genes. This is because information flows from genes through an intermediate RNA molecule, and is translated to construct proteins. Variations that disrupt this flow could have dramatic consequences. Using bioinformatics (analysis of genetic data using advanced computing algorithms), Dr. Wasserman aims to identify regulatory variations that likely impact gene function and contribute to genetic diseases.
Identification of the roles played by NIMA-related kinases in flagellar, microtubule, and cell cycle regulation and signalling in Chlamydomonas
NIMA-related kinases are a diverse family of proteins found in virtually all eukaryotic cells. Single-celled eukaryotes, such as yeast, have a single NIMA family member that helps regulate cell division. A recent discovery that Chlamydomonas, a single-celled green algae, has at least seven family members strikingly contrasts with other unicellular organisms. What sets Chlamydomonas apart from the other unicellular eukaryotes studied to date is the presence of cilia. Mutations in some NIMA kinsases can produce kidney cysts, as do mutations in the proteins essential for assembling cilia, short, hair-like structures that protrude from cell walls and sweep mucus up and out of lungs. In earlier research, Brian Bradley helped identify six new genes in Chlamydomonas. These algae are found all over the world, and are often used for research in cell and molecular biology. Now Brian is using the algae to study the assembly and function of cilia. Brian’s research could help explain the role of NIMA-related kinases in development of kidney disease.
Truncation of huntingtin and its relationship to the pathogenesis of Huntington's Disease
Huntington disease (HD) is a fatal degenerative brain disorder caused by a defective gene, which causes cells in specific parts of the brain to die. This leads to symptoms including progressive deterioration in the ability to control movements and emotions, recall recent events or make decisions, and leads to death 15 to 20 years after onset. One in 10,000 Canadians has HD, and children with a parent with HD have a 50 per cent risk of inheriting the disease. There is neither a cure nor treatments to prevent Huntington disease. The HD gene produces a protein called huntingtin, which breaks into short fragments that dramatically promote cell death. Little is known about the exact function and toxic properties of this mutant protein. Now Rona Graham is expanding her earlier Masters research into the mechanisms that cause shortened huntingtin. She is investigating other forms of mutant huntingtin to determine their role in creating HD, and hopes the results will lead to new therapies to prevent or alleviate this disease and other neurodegenerative disorders.