Research Location: Jack Bell Research Centre

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which insulin-secreting islet beta cells of the pancreas are destroyed by a type of white blood cell called a T cell. While most people with T1DM must receive insulin injections to maintain proper blood glucose levels, a recent option for some patients is to undergo islet transplantation, which replaces the insulin secreting cells they have lost with new donor cells. However, the immunosuppressive drugs required to prevent graft rejection are costly and have serious side effects. Researchers continue to search for new methods to achieve long term transplant survival. T regulatory (Treg) cells have great potential to protect islet grafts from rejection. Treg cells are a subset of white blood cells with the capacity to suppress immune responses. It has been shown that a key protein named FOXP3 is essential for the development and function of Treg cells. T cells expressing this protein can reduce autoimmune disease and reverse established diabetes in mice. Researchers recently developed a method for converting human T cells into Treg cells. Alicia McMurchy is generating human Treg cells and testing their ability to inhibit graft rejection in a mouse model. Her prediction is that the generated Treg cells will inhibit graft rejection and allow long-term survival of transplanted islets. If validated, this approach could indicate a promising future for clinical use of Treg cells in transplantation, potentially alleviating the need for expensive and harmful immunosuppressive drugs and improving the health and quality of life of T1DM patients and other transplant patients.

Wound Healing in skin is a dynamic process that involves continuous sequences of signals and responses from cells like fibroblasts and keratinocytes. An imbalance in the signals and responses at the wound site may result in an over-healing process known as hypertrophic scar.

This scar, thick and fibrous, might inhibit movement when it results from serious burns over large areas, especially around a joint. In hypertrophic scars, the fibroblasts produce too much extracellular matrix (ECM) proteins – the “scaffolding” between cells – including collagen. They also produce too little matrix metaloproteinases (MMP), an enzyme involved in normal tissue breakdown and remodeling.

Keratinocytes are epidermal cells that release factors that will either prompt fibroblasts to produce MMP or keep them from producing collagen. Previous research has identified a factor called stratifin, which stimulates MMP production. However, the factors associated with the inhibition of collagen production have not yet been described.

Claudia Chavez-Munoz’s research seeks to identify and characterize the keratinocyte-derived factor(s) that may function as collagen inhibiting factors for dermal fibroblasts. Ultimately, she hopes that a better understanding of the factors involved in wound healing will lead to therapeutic strategies in order to improve or prevent hypertrophic scarring.

Cutaneous malignant melanoma is a life-threatening skin cancer that is very resistant to conventional radio- and chemotherapy and has a low survival rate. Thus, it is important to understand the molecular changes underlying the onset and progression of the disease. The novel tumour suppressor ING3 acts to inhibit cell growth. A number of previous studies have demonstrated that ING3 switches on and off during normal cell division, and that it enhances cell death in melanoma cells when they are exposed to UV-light. Dr. Guangdi Chen has identified that the expression of ING3 degrades (or decreases) much faster in melanoma cells than in regular melanocytes (healthy melanin-producing cells) during the cell cycle. This rapid degradation may be an important cause of aberrant ING3 expression and the loss of its tumour suppressing function. However, the mechanism of ING3 protein degradation and its role in cell cycle progression remain unclear. Chen is investigating the pathway of ING3 protein degradation and assessing its role in cell cycle progression. By understanding the molecular mechanisms of ING3 tumour suppressive functions in cell cycle progression, he hopes his work could help in the design of novel strategies for cancer prevention and treatment. Chen’s post-doctoral fellowship is jointly funded by MSFHR and the VGH & UBC Hospital Foundation.

In 2006, it was estimated that 153,100 new cancer cases were diagnosed in Canada, and 70,400 patients died of cancer. Improving our understanding of the molecular changes in cancer development is essential for designing more effective strategies for cancer prevention and treatment. In the past few years, studies on the biological functions of the tumour suppressor ING1b have attracted much attention in the scientific community. Dr. Aijaz Wani and his colleagues have found that ING1b can enhance DNA repair and promote programmed cell death – key biological functions that prevent cancer cells from developing and growing. However, information on the regulation of ING1b expression and its activity is lacking. Wani’s recent studies have uncovered that that the amino acid serine 126 attaches a phosphate group to ING1b, a process known as phosphorylation. He also confirmed that serine 126 phosphorylation is essential for ING1b protein stability. Now, he is investigating in detail how serine 126 phosphorylation of ING1b regulates the biological functions of this tumour suppressor. Wani’s research will provide new insights into the mechanisms on the regulation of ING1b activity and its biological functions. Ultimately, this work may lead to novel strategies for cancer prevention and treatment.

In mammalian cells, DNA is packaged into a tight structure called chromatin. The DNA in cells can be damaged by a number of agents, including ultraviolet light, and failure to repair damaged DNA can lead to genetic mutations that can kill cells or induce cancer formation. In order for core DNA-repair proteins to access damaged genetic material, the condensed chromatin structure must be relaxed. The protein ING1b (a growth inhibitor) is known to enhance the repair of DNA in ultraviolet-injured cells by relaxing the chromatin structure. Conversely, mutations in the ING1b gene within a region called the PHD finger have been shown to reduce DNA repair and have also been correlated with reduced survival of patients with melanoma (an aggressive form of skin cancer). Building on the research findings of his supervisor, Dr. Gang Li, William Kuo is studying the mechanisms through which ING1b assists DNA repair. He hypothesizes that ING1b associates with a class of chromatin-modifying protein complexes, called histone acetyl transferase (HAT) to induce chromatin relaxation. He will also explore the possibility that the PHD finger tethers the ING1b-HAT complex to chromatin for its relaxation during DNA repair. He hopes that an understanding of these mechanisms could lead to the development of new therapies for cancers caused by damage to DNA.