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.

Impact of delayed childbearing in BC, Canada

Women in developed societies around the world increasingly delay childbearing until the age of 35 or older. In BC, women who are 35 or older account for about 8,000 births a year. There has been little research into the effects of delayed childbearing, and studies that have been undertaken produced contrasting results. Some research suggested an increased risk of complications and other studies showed no greater risk. No research has compared differences in rural and urban settings. Sarka Lisonkova is investigating the impact of delayed childbearing on pregnancy outcomes and infants’ need for health care services in their first year. Using information on 200,000 births across the province from the BC Perinatal Database Registry, Sarka is comparing outcomes and health care utilization from births among 20 to 34-year-old mothers with those 35 and older. She is also reviewing the effect of risk factors for adverse pregnancy outcomes, such as smoking and fertility problems. The research could help improve prenatal counselling and risk assessment in prenatal care.

Developmental changes in pain expression in infants

Assessing infant pain for clinical or research purposes is challenging because infants are unable to talk about their pain. However, infants can communicate distress and pain in a number of ways, including facial activity, body movement, crying and changes in physiological responses. Rami Nader is studying how pain expression changes during the first year of life, when infants undergo a particularly rapid rate of growth and development. He is also investigating the link between parents’ assessments of pain and factors that influence those assessments. Improved understanding of how infant pain expression changes and what influences parents’ reports of pain will contribute to refinement and development of more developmentally appropriate measures of pain.

FIND: Fundamental Innovation in Neurodegenerative Diseases

The goal of this research unit is to understand the molecular mechanisms leading to neuronal (brain cell) death in Huntington Disease, an incurable genetic disorder that usually strikes in mid-life, causing progressive, irreversible and ultimately fatal neurological damage. With a focus on the fundamental molecular structure and function of neurons, such research also has relevance in understanding the development and effects of other degenerative neurological disorders, such as Alzheimer’s and Parkinson’s Disease, and for understanding recovery from brain injury. As the study of disease reveals information about normal structure and function, this research will also contribute new knowledge about healthy brain development.

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Understanding low-income mothers' efforts to provide safe home environments for young children

Unintentional injuries represent the leading cause of death for children and youth under the age of 20. For children under five, approximately half of all deaths due to unintentional injuries occur in and around the home. Research shows that children living in low-income families are at greatest risk for home injuries. Studies also show that parental attitudes towards safety issues vary greatly, and that there are discrepancies between attitudes and taking action to prevent injuries. However, little is known about parents’ underlying values about safety and injury risks to young children and how these values fit into the broader social context of children and safety issues. Lise Olsen is exploring low-income mothers’ experiences with safety issues in the home. Using ethnographic methods, including interviews and observations, the study will provide insight about the everyday challenges of keeping young children safe from injuries at home. Ultimately, Lise hopes the research contributes to the design of appropriate and relevant injury prevention programs and policies.

Agonist-specific Ca2+ signalling micro-domains in vascular smooth muscle cytoplasm and mitochondria

Building on his earlier research, which was supported by a MSFHR Trainee Award, Damon Poburko is now investigating the mechanisms involved in mitochondrial regulation of calcium. An average cell has several hundred mitochondria, which provide the energy for cells to function properly. Research has shown mitochondria are involved in programmed cell death, or apoptosis, when they take up large, toxic loads of calcium. In addition, mitochondria sense calcium changes, allowing them to tailor energy production to cell needs. Mitochondria also help regulate intracellular calcium levels, which determine blood vessel constriction in vascular muscle. The findings should help explain how vascular tone is regulated, and how blood is shunted to different parts of the body as needed. Ultimately, this research may lead to the development of new therapies to treat vascular diseases.

Characterization of a YAC mouse model of Huntington disease for use in therapeutic trials

Huntington disease (HD) is an inherited, neurodegenerative disease characterized by loss of motor control and cognitive decline, eventually leading to death. Elizabeth Slow is studying atrophy and cell loss in the striatum, the most affected region of the brain, and the motor dysfunction associated with HD. A group of proteins called caspases split other proteins, including huntingtin, the protein produced by the HD gene. In collaboration with researchers at Harvard, the University of California and the Buck Institute in California, Elizabeth is investigating whether this process triggers inappropriate cell suicide in the neurons affected by HD, thus causing the disease. If so, the results will determine whether caspase inhibitors are an effective treatment option for people with Huntington disease, which currently has no treatments to prevent or delay the condition.

Pathogenesis of confined placental mosaicism (CMP) during pregnancy

The frequency of chromosomal abnormalities in reproduction is significant — 15 to 20 per cent of all pregnancies end in spontaneous abortion, and half of these miscarriages are associated with chromosomal abnormalities. In 1983, two UBC professors discovered a condition now known as confined placental mosaicism (CPM), where a chromosomal abnormality is present in the placenta but not the fetus. CPM allows a pregnancy that would otherwise spontaneously abort to continue to term, and is present in at least two per cent of pregnancies. In his earlier research, Paul Yong confirmed that some types of CPM increase the risk for poor fetal outcomes such as low birth weight or complications such as pre-eclampsia. Now he is studying how chromosomal abnormalities cause alterations in placental structure and function. The hope is to identify potential therapeutic interventions in pregnancies affected by chromosome abnormalities in the placenta.

Early progression and detection of ovarian cancer

In developed countries, ovarian cancer is the leading cause of death from gynecologic malignancies in women. The five-year survival rate is only 35 to 40 per cent, a rate that hasn’t changed significantly in 25 years. The poor prognosis is due to the lack of a reliable test for early detection and the inability to identify early symptoms of the disease, which means the majority of ovarian tumours are diagnosed at an advanced stage. During progression to malignancy, normal ovarian surface epithelial cells, which give rise to the majority of epithelial ovarian cancers, acquire more complex and highly differentiated characteristics that most often resemble epithelial cells in the fallopian tube and uterus. This change may provide an advantage for growing cancer cells. Michelle Woo is screening ovarian tumour tissues for markers known to be present in the fallopian tube and uterus. She has recently discovered a protein in ovarian tumours that may be an early indicator of ovarian cancer. Another approach she is using to examine early changes in ovarian tumour progression involves the use of a unique three-dimensional culture system to mimic the development of ovarian tumours in women. Michelle hopes this research will identify new predictive markers that can be used for early screening and prevention of ovarian cancer.

Toxicogenetic analysis of valproic acid-associated hepatotoxicity in pediatric epileptic patients

Valproic acid is a drug that has been used successfully for the treatment of many types of seizures. Yet for some patients, the drug is associated with liver failure. Clinicians are not able to predict which patient will be at risk for this serious and sometime fatal side effect, but it is known that liver failure is more common in the very young patients and when the drug is used together with other anticonvulsants. Tony Kiang is studying the possibility that individuals could have a genetic predisposition for developing liver failure following valproic acid therapy. In his research project, Tony will be using advanced genomic technologies to test this hypothesis. Results from this research will help clinicians identify which patients are suitable to be prescribed valproic acid.