More than 95% of the human genome is made up of non-coding DNA, historically dismissed as âjunk DNAâ of unknown function. It is now known that the so-called junk DNA isnât junk at all; in fact, it contains important information specifying how genes are regulated. Non-coding DNA sequences located adjacent to genes typically contain binding sites for proteins that act like regulatory switches, turning genes on or off in the appropriate cell types and under particular conditions. Errors in this process have been linked to diseases ranging from cancer to obesity. Recent studies have determined that there are a surprisingly large number of non-coding sequences that are highly conserved across the vertebrate lineage. These regions, termed âultraconserved sequencesâ, are almost identical in humans, rodents and fish. They have been minimally explored but appear to have an important role in regulating the expression of key developmental genes. Shannan Ho Sui is studying the properties of ultraconserved regions in the human genome to assess their potential role in gene regulation. Her research involves using bioinformatics techniques to find and analyze patterns in DNA sequences. By determining the properties of genes associated with ultraconserved regions, evaluating how frequently recombination occurs in these regions, and locating similarly highly conserved non-coding sequences in the fly and worm genomes, Shannan hopes to develop a model describing how and why these regions are maintained in the genome. Her research results will provide valuable insights into mechanisms of gene regulation that play important roles in development and disease.
Research Location: Children's & Women's Health Centre of British Columbia
The role of protein tyrosine phosphatase alpha (PTPa) in integrin signaling in fibroblasts
Communication between the outside and inside of cells relies on protein molecules (such as integrins) at the cell surface, which interact with the external environment and send signals to other molecules inside the cell. These molecules interact to form complex signaling cascades to effect appropriate cell responses. Protein tyrosine phosphatases (PTPs) are a family of proteins that play a critical role in cell signaling processes. Shirley Chen is investigating the function of PTPalpha, an important player in integrin signaling. This signaling pathway regulates cell growth, migration, and survival, and has been implicated in cancer development and progression. By studying the activity of PTPalpha-deficient cells in comparison to normal cells, she will learn more about the role of this protein in the integrin signaling cascade. Since integrin signaling governs several aspects of how a cell responds to the environment, her study of this process will help reveal why certain cells, such as cancer cells, behave abnormally. In the long term, her research could contribute to understanding the onset and course of diseases such as cancer and diabetes, and may potentially lead to PTPalpha-based therapeutics for these diseases.
An investigation into priority setting by hospital formulary committees in British Columbia: what weight does evidence carry in the face of competing factors?
Some health care services are prioritized at the expense of others, due to limited resources. Many decision makers set priorities for allocating resources based on evidence derived through health economics and clinical research. The trend towards evidence-informed health policies has gained considerable momentum in Canada, particularly with pharmaceutical policy because drugs are a major cost driver in the health system. It is clear, however, that health policies are not determined solely on the basis of health research evidence. Kristy Armstrong is examining the roles played by evidence and other factors â such as an institutionâs values, and the interests of key stakeholders â during decision making about drug coverage in both a regional health authority and a hospital in British Columbia. This study will help clarify the environment in which health policy is set and potentially point to ways of more effectively integrating use of evidence in decision making.
The American Society of Addiction Medicine – patient placement criteria, second edition revised (PPC- 2R) validity study in Canadian women
Mental health and addiction services have experienced frequent budget cuts in recent years, as governments try to contain health care spending. Yet, as Dr. Shimi Kang discovered during her earlier research at the World Health Organization in Geneva, Switzerland, substance use and mental illness are major global public health issues. The American Society of Addiction Medicine (ASAM) has developed a software program for making treatment decisions that consider resource issues. The program prompts interviewers to ask a series of questions, and produces recommendations for matching patients to the most appropriate treatment setting, based on standardized criteria. The software is now widely used in the United States, and studied in several other countries. However, the effectiveness of this assessment tool has never been studied within the Canadian health care system or with women, who experience different rates of addictive disorders and mental illness than men. Shimi is conducting the first Canadian study to evaluate whether the program can be applied to assess the complex biological, psychological and social needs of women with mental health and addiction problems. The results may lead to better techniques for treating drug and alcohol addiction and preventing relapse in women.
Role of the tumor suppressive E3 ubiquitin-protein ligase, Hace 1, in the development of childhood neoplasm
The onset and growth of a tumour may be due to the destruction of the balance that is normally achieved between tumour promoting and tumour suppressing factors. Recently, Dr. Poul Sorensonâs research team discovered a new gene, Hace1, from a case of Wilms’ tumour (the most common kidney tumour of childhood). They also found that Hace1 protein levels were reduced in 75% of the Wilms’ tumours analyzed, and that the restoration of Hace1 levels in tumour cells was capable of inhibiting tumour growth. These findings suggest that Hace1 is a tumour suppressive factor and that loss of Hace1 may contribute to the development of childhood tumours. However, the mechanisms by which Hace1 inhibits tumour formation are not yet understood. Current research suggests that Hace1 is an enzyme that specifically labels target proteins with small protein tag(s) called ubiquitin. It is thought that alterations of this process, as in the reduction of Hace1 levels observed in Wilmsâ tumour, may lead to malfunctions of the target proteins and facilitate tumour development. Dr. Fan Zhang is testing this hypothesis through the identification of Hace1 target proteins and analysis of the Hace1 function in both normal and tumour cells. The knowledge derived from this study will help researchers understand how loss of Hace1 leads to the formation of childhood tumours which, in turn, may lead to new preventive treatment based on correcting the imbalance between tumour promoting and tumour suppressive factors.
Nutrition Research Program
Dietary components are powerful determinants of health, affecting every aspect of human function from regulation of gene function to growth, physical and cognitive performance as well as our susceptibility to and ability to recover from disease. The Nutrition Research Centre at the Child and Family Research Institute on the site of BC’s Children’s & Women’s Health Centre is exploring the development of innovative nutritional strategies for preventing and managing disease, and for supporting children to achieve their maximum potential for physical and neurological development and health throughout life.
Childhood Diabetes Research Unit
More than 1,000 children in BC have Type 1 diabetes. Type 2 diabetes, which typically has been regarded as the adult form of the disease, is on the rise in children. Researchers in this unit are investigating new ways to predict, prevent and treat diabetes in children, with the ultimate goal of finding a cure.
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.
Cervical cancer and sexuality: effects of a psychoeducational intervention and sildenafil on sexual arousal, relationship satisfaction and quality of life after hysterectomy
More than 25 percent of women who have a radical hysterectomy (surgery to remove the uterus, cervix, and upper vagina) as part of treatment for cervical cancer develop sexual difficulties related to genital arousal. There are no established treatments for these sexual problems leaving women with chronic distress. Dr. Lori Brotto has developed and is assessing whether a psycho-educational treatment can improve sexual arousal in these women. She is also assessing the effectiveness of combining the treatment with sildenafil citrate (Viagra). Dr. Brotto aims to incorporate qualitative feedback with psycho-physiological and self-report measures on the effectiveness of the psycho-educational treatment in hopes of improving clinical practice. The research could help improve sexual health, mood, and overall quality of life for cancer survivors and their partners. It could also broaden understanding of womenâs sexuality and guide future research to better address womenâs sexual health care needs.
Behaviour of the newborn infant in response to pain, distress and caregiving influences
Recent evidence suggests newborn infants are more sensitive to pain and stress than older children and adults. The level of sensitivity may be especially acute for newborns who are at-risk for developmental problems due to prenatal exposure to pain, antidepressants or illicit drugs. Studies suggest that early exposure to pain and stress leads to changes in the newbornâs brain circuitry, and may increase vulnerability to abnormal behaviour and development. This has led to a search for better ways to understand and recognize infant pain and measure the effects of pain treatment. Dr. Fay Warnock is investigating the actions and interactions of healthy and at-risk infants. The research involves confirming a comprehensive list of behaviour associated with newborn distress, and comparing the actions of healthy and at-risk newborns during and after routine diaper change and heel lancing, a common procedure for obtaining a blood sample to screen infants for metabolic errors. She is also linking newborn behaviour with changes in facial action and heart rate. The research will further develop measures of newborn pain, improve understanding of how caregivers can help alleviate pain, and lead to protocols for preventing, assessing and treating newborn pain.