Pre-mRNA splicing is a critical step in the process by which genes direct the production of proteins. While there are many aspects of this process we do not yet understand, it is clear that splicing must be incredibly accurate. Errors can result in a number of devastating diseases, including myotonic dystrophy, spinal muscular atrophy and retinitis pigmentosa, which results in blindness. Splicing errors have also been linked to the growth of malignant tumours and the development of cystic fibrosis and Alzheimer’s disease. Amy Hayduk’s research at the Rader Lab at the University of Northern British Columbia is directed at understanding the mechanisms that make up the process. Specifically, she is using molecular beacons to study the roles of the four RNA recognition motifs of the protein Prp24. This work builds upon original research conducted by Hayduk involving a novel application of molecular beacon technology to RNA detection. By analyzing the degree of impairment in the activity of Prp24 resulting from specific gene mutations, her work will help explain the molecular interactions through which pre-mRNA splicing is accomplished. By contributing to a more precise understanding of the intricate sequence of molecular interactions that constitutes pre-mRNA splicing, this research will assist with the development of strategies for treating diseases that arise from defects in splicing.
Year: 2007
PTEN Regulates Alternative Splicing
Prostate cancer is the most common non-skin cancer among Canadian men and the second leading cause of cancer death. Prostate cancer starts in the prostate gland, part of the male reproductive system. Frequently, men with early prostate cancer have no warning symptoms. PTEN is a tumour suppressor gene that has been linked to prostate cancer. PTEN helps promote apoptosis (cell death), which helps regulate the uncontrolled cell growth that occurs in cancer; unfortunately, PTEN is often mutated in advanced stages of prostate cancer. Alternative splicing is an integral part of normal cell function, and is important for generating protein diversity and controlling protein function. Tien Yin Yau’s study investigates whether PTEN plays a role in regulating alternative splicing. Yau is studying whether changes in normal mRNA splicing increase susceptibility to prostate cancer by affecting genes implicated in tumor progression. The findings of Yau’s study will increase our knowledge of the molecular mechanisms that regulate alternative splicing. Understanding what changes occur and their effects may result in the development of more effective cancer treatments.
Molecular Epidemiology of Gastric and Esophageal Cancer Survival
Cancers of stomach and esophagus (the tube from the mouth to the stomach) are a major cause of illness and death. Worldwide, the incidence of tumours at the stomach-esophagus border is increasing more rapidly than any other type of cancer. Historically, gastric and esophageal cancers have been studied separately; however, recent evidence suggests these cancers have a lot in common. As a result, studying these cancers together may result in information about the origin or effective treatment of one cancer having similar implications for the other. Morteza Bashash is investigating whether certain genes are associated with the disease progression of these cancers. Specifically, he is testing whether these patients have alteration of two groups of genes that are associated with cancer progression, Matrix Metalloproteinase (MMP) and Tissue Inhibitors of Metalloproteinase (TIMP). He is monitoring newly-diagnosed patients to determine whether the progression of the disease depends on these genes or other possible determinants such as family history, and/or the patients’ ethnicity. He is also assessing whether the effects are different in geographic areas where the cancers are becoming more common (BC), and areas where the cancers are already common. The results from this research could help identify high risk patients and provide them with more effective treatment.
Goal adjustment processes and caregiver health: Can giving up be a good thing?
Mounting evidence indicates that caring for a family member with a chronic illness not only reduces the quality of life for the caregiver, it also increases the caregiver’s risk of becoming ill. Little is known about the specific mechanisms by which caregiving impacts health and well-being. One important factor may be the caregiver’s ability to adjust personal family and career goals to meet the demands of the difficult situation. If a caregiver is able to let go of goals set before the diagnosis, such as getting a promotion at work or building a vacation home, he or she may have an easier time adjusting to this new role, and in turn, experience reduced distress and better physical health. Teresa Marin is examining the impact of tendencies to adjust goals on both psychological and physical well-being. Once she has determined the relationship between goal adjustment and health in the context of caregiving stress, it will be possible to apply this knowledge to clinical interventions designed to foster better coping skills among caregivers. This research follows Marin’s MSFHR-funded Master’s work, in which she analyzed the mental and physical health of spouses caring for cancer patients to determine the daily impact of expressing or suppressing their emotions.
Transcriptional regulation of genes in health and disease
The human genome contains all the genes, and their regulatory instructions, required to develop the human body and determine how it deals with the outside environment. Now that the genomes of many species have been sequenced, a major focus of genomics is to identify all gene regulatory elements within DNA sequences. How these building blocks of life work together to build a complex human body – with its different organs, tissues, and cell types – is not well understood. Although most human cells carry the entire genome, each cell is functionally different, suggesting that not all genes are equally expressed.
Gene expression – the full use of information in a gene – is regulated in several ways, including by transcription. Specific regulatory proteins called transcription factors bind to targeted DNA sequences in the genome. This kind of activity can control cells by switching gene expression on and off. To better understand transcription regulation in genes, and thereby better understand gene expression, binding sites for transcription factors have to be identified. It is a fundamental step in the analysis of gene expression, which is tightly regulated so that genes are only expressed in specific cells, at specific developmental stages, and at appropriate levels to ensure correct physiological function.
Dr. Jack Chen’s work investigates the properties of transcription factor binding sites (TFBSs) and determines how these properties can assist with effective genome-wide TFBS identification. Using the nematode C. elegans as the model organism, he will combine experimental and computational approaches to characterize the properties of TFBSs that distinguish functional DNA sequences from nonfunctional ones. This study may pave road for a deep understanding of transcription in C. elegans, which will in turn shed light on both healthy and dysfunctional transcription in humans.
Mechanisms of X-linked Dyskeratosis congenita
Dyskeratosis congenita (DC) is an inherited premature-aging syndrome that typically results in bone-marrow failure. Symptoms include abnormal skin pigmentation, abnormal or absent nails and white, pre-cancerous areas on the lips and in the eyes, mouth and other body openings. More than 80% of patients with DC develop bone-marrow failure, which leads to decreased production of all types of blood cells. Premature death is usually the result of bone marrow failure. Most cases of DC are caused by changes in the DKC1 gene on the X chromosome. DKC1 encodes a protein called dyskerin, which helps maintains chromosomes, in addition to its essential function of manufacturing protein synthesis machinery. A symptom-free mother carrying a DKC1 mutation has a 50% chance of transmitting it to a son who will develop the disease.
Using genetic and biochemical techniques, Dr. Judy Wong is working to determine the mechanisms of X-linked DC. There are more than thirty amino acid mutations of the dyskerin protein that are known to be associated with X-linked DC. Understanding the molecular events that give rise to X-linked DC will help predict how patients will be affected and assist in the development of genetic therapies. Dr. Wong plans to test the effectiveness of dyskerin gene replacement techniques in restoring normal activity in X-linked DC cells. Her work will also improve our understanding of how other physiological factors can compromise normal aging.
The Genetics of Asthma, Atopy and Allergic Diseases
My research focuses on trying to identify why some children get asthma and others do not. By identifing specific environmental and genetic risk factors and determining how they work together to predispose children to developing asthma and other allergic diseases we can design better treatments. Studies have found a 1-in-5 risk of developing asthma if one parent has asthma. The odds rise to 2 out of 3 if both parents have asthma. However, in itself, a genetic predisposition does not ensure that asthma will develop. Asthma and allergic disease are the result of both genetics and the environment. The interaction between a genetic disposition and environmental factors is key in the development of – or in protecting against- asthma. I will use information from 250 French Canadian Asthma Families and two additional birth cohorts, and information from the town of Busselton Australia in my research. Home visits were conducted for all the families and children to collect information on environmental factors such as family history, number of children, parental occupations, daycare, pets, dust samples, infections, hospitalizations and medication usage. After reviewing the literature we have found 162 genes which may predispose children to developing asthma and we will be looking at these genes in conjuction with other environmental factors to try and better understand why some children develop asthma and others do not. Using statistical models we will look at what genetic and environment factors best explain why some children develop asthma and others do not. We will then do further laboratory experiments to try and identify these factors work together.
An examination of illicit drug use and sexual risk behaviours among a cohort of street-involved youth in Vancouver
Injection drug use has significant health consequences, including high rates of HIV and hepatitis C transmission. These problems have been exacerbated in recent years by the use of crystal methamphetamine (commonly called crystal meth), particularly in BC. Methamphetamine use is becoming increasingly common among marginalized youth, particularly those whose social and economic environment is the street. It is estimated there are between 45,000 to 150,000 street-involved youth in Canada, most of whom live in the large urban centres of Toronto, Montreal and Vancouver. Illicit drug use and unsafe sexual practices, including unprotected sex and sex trade work, increase susceptibility to HIV infection among street-involved youth. Brandon Marshall is one of the few researchers investigating the relationship between illicit drug use and sexual risk behaviours among street-involved youth. Using data collected from the B.C. Centre for Excellence in HIV/AIDS At-Risk Youth Study, he will examine how different social, structural, and environmental factors impact sexual practices. Specific factors include the age of first sexual experience, sexual orientation, illicit drug use, sexual relationships with older partners, access to health services, and involvement in the Downtown Eastside community of Vancouver, where drug use and poverty are prominent. This research will improve our understanding of illicit drug use and sexual activity in marginalized youth and will play an important role in developing sexual health education and prevention programs for youth at-risk.
To define the role of caspases and caspase cleavage of htt in the pathogenesis of HD
Research has identified a genetic defect in the HD gene that causes Huntington’s disease, a devastating and ultimately fatal neuropsychiatric disease. Symptoms include 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. There is neither a cure nor treatments to prevent Huntington disease. Several years ago Dr. Hayden and his team discovered that huntingtin, the protein involved in Huntington disease (HD), is cleaved by ‘molecular scissors’ which are proteins called caspases. This discovery led to the hypothesis that cleavage of huntingtin may play a key role in causing HD. To explore the role of huntingtin cleavage in the disease process, we established an animal model of HD that replicated the key disease features seen in patients. A unique aspect of this particular animal model is that it embodied the human HD gene in exactly the same way seen in patients. This replication allowed researchers to examine the progression of HD symptoms including the inevitable cleavage of the mutant huntingtin protein. Dr. Rona Graham is continuing her earlier MSFHR-funded research into understanding the reason why the mutant form of the HD gene causes death of particular neurons in the brain. Her Masters and PhD work demonstrated that preventing cleavage of the mutant huntingtin protein responsible for HD in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function. Dr. Graham’s goal now is to investigate the role of caspase activation and the caspase-6 cleaved huntingtin fragment in the disease process. Since a similar splitting of disease proteins is involved in many other central nervous system diseases including Alzheimer’s and Spinocerebellar ataxia (which causes progressive deterioration in hand, speech and eye movement) Dr. Graham hopes the findings will lead to new treatments for other neurological disorders as well as HD.
Independence of identity and expression? A look at facial processing in both healthy and patient populations
Recognizing facial expressions and identities plays a crucial role in daily life. People who have experienced damage to identity recognition regions of the brain due to stroke, trauma or other causes are unable to recognize the identity of faces, often including their own. People with damage to regions involved in expression recognition have difficulty interpreting expressions, which leads to social mistakes. Problems in expression recognition may have a role in autism and other social developmental disorders. Studies have suggested that specific brain regions are primarily involved in either facial identity recognition or facial expression recognition. However, recent studies, including research Christopher Fox has contributed to, suggest the two are not restricted to independent regions. Fox is designing a series of psychophysical tests to determine the extent of the overlap and using functional magnetic resonance imaging to measure brain activity in both healthy individuals and those who have experienced brain damage. Fox aims to determine whether an area of the brain previously thought of solely as an expression recognition region is also able to process facial identity. The research could lead to new therapies for people with facial recognition disorders. Fox was funded as a 2005 trainee award recipient for research on the role of the temporal lobes in vision and the process of visual perception.