Research Location: Children's & Women's Health Centre of British Columbia

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.

More than 95% of the human genome is made up of non-coding DNA, historically dismissed as ‘junk DNA’ of unknown function. It is now known that the so-called junk DNA isn’t 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 ‘ultraconserved sequences’, 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.

Atherosclerosis is a slow, progressive disease caused by the buildup of plaque (fatty substances, cholesterol, cellular waste products, calcium and other substances) in the inner lining of the arteries. This plaque buildup can lead to heart attack, stroke or gangrene. Research has shown that high-density lipoproteins (HDL) remove excess cholesterol from plaque by transporting cholesterol away from the arteries and back to the liver, thus slowing the buildup. Higher levels of HDL seem to be protective against coronary artery disease, and thus HDL is sometimes referred to as “”good”” cholesterol. Dr. Roshni Singaraja is researching the role of the newly-discovered gene ABCA1, whose function is to to produce HDL. Specifically, she is investigating the role of the palmitoylation process (the attachment of palmitate – fatty acids – to proteins which acts as a signal for the protein to be transported) on ABCA1 and its function. In addition, Roshni will examine the function of ABCA1 in the brain and the impact of palmitoylation on these functions. Roshni’s research may lead to potential strategies to increase HDL production and to accelerate or reverse cholesterol transport in order to prevent atherosclerosis.

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.