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 Sorenson’s 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 Wilms’ 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.

Creation and function of neighborhoods in eukaryotic chromosomes: regulation by SWR1-Com, a desposition complex for histone variant H2A.Z

Chromatin is the complex of DNA and protein material that make up chromosomes, home to the genetic code. The basic unit of chromatin is the nucleosome, a fundamental building block consisting of DNA wrapped around an octamer of histone proteins. A large number of proteins involved in cancer development and the genetic susceptibility to devastating diseases such as Ataxia Telangiectasia (a progressive immunological and neurological disorder) act through modification of chromatin structures and interfere with normal chromatin function. Differences in chromatin structures between adjacent regions specify the properties of larger macrodomains called neighbourhoods. The shape and structure of these neighbourhoods influence chromosome behavior, while complex regulatory mechanisms that ultimately involve chromatin ensure that each cell expresses only the appropriate genes, duplicates its genome with high fidelity, divides only when required, all while combating constant assaults on its DNA. Failure in any of the mechanisms regulating these events can lead to disease. These chromatin structures themselves can also be inherited, creating an additional complex set of influences that are crucial for the identity and activity of the cell. The molecular biology of chromatin structures and their role in chromosome biology and genome function in health and disease is the focus of Michael Kobor’s research. Specifically, he is studying a unique chromosomal neighbourhood containing a specialized histone variant known as H2A.Z, which is deposited into chromatin by a large protein complex. Using innovative genome-wide approaches, Dr. Kobor’s team aims to uncover the rules and principles of histone variant function.

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.

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 women’s sexuality and guide future research to better address women’s 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 newborn’s 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.

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.

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The nature and extent of genetic discrimination for presymptomatic individuals identified with an increased risk for Huntington's disease

A genetic test predicting onset of Huntington’s Disease (HD) has been available since 1986. Reports of discrimination resulting from genetic test results have been documented in the US and Great Britain and, while there are no published reports of such discrimination in Canada, research suggests that it occurs here as well. Yvonne Bombard is investigating discrimination faced by Canadians who test positive for genetic risk of HD, but have not yet developed outward symptoms. She is assessing the degree of discrimination they experience when trying to obtain extended health coverage, life and disability insurance, and employment, and comparing these findings to discrimination levels in the US and Australia. Results from the research could be used to inform social, legal and health policy related to predictive genetic testing.

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.