Structure and RNA-cleaving function of apurinic/apyrimidinic endonuclease 1 (APE1)

Cancer occurs when cells won’t stop growing. The source of this malfunction is often an alteration in DNA, the genetic instructions for making different proteins inside a cell. To make proteins, a gene is copied out from the DNA into a molecule called mRNA. The mRNA travels out of the cell nucleus and into the cytoplasm, where its genetic instructions are used as a template for synthesizing proteins. C-myc mRNA serves as a template for synthesizing the c-Myc protein. This protein plays fundamental roles in regulating growth, differentiation, and cell death in virtually all mammalian cells, and it is implicated in diverse human cancers. In fact, it has been estimated that c-Myc dysfunction contributes to one-seventh of all cancer deaths. One way that cells regulate their level of proteins is by destroying mRNA in the cytoplasm by chemically cutting, or cleaving, its molecular structure. Recently, the enzyme APE1 was discovered to cleave c-myc mRNA. This opens the potential for using APE1 to reduce or eliminate levels of c-Myc protein in the cytoplasm as a potential treatment for cancer. Wan Kim is exploring the function of APE1 as an mRNA destroyer. He is identifying the key amino acids and mechanisms APE1 uses to cleave c-myc mRNA, and determining whether the enzyme cleaves any other types of mRNA. Kim hopes to generate valuable insights into how APE1 can degrade c-myc mRNA and influence gene expression. Also, the study will provide useful information on the potential design of novel approaches in cancer treatment.

Vascular dysfunction of the arteries in a mouse model of Marfan syndrome

Marfan syndrome is an inherited disorder of the connective tissue that causes abnormalities of the eyes, cardiovascular system, and musculoskeletal system. Its most serious and deadly complication is ballooning and rupture of the aorta, the major blood vessel that carries blood from the heart to the arteries and organs. The syndrome is caused by a defect in the gene that makes fibrillin-1 protein. Fibrillin-1 is essential in the formation of elastic fibres in arteries and in maintaining the functional and structural integrity of blood vessels’ endothelial and smooth muscle cells. Defects in this gene result in abnormalities in the way vessels contract and relax, increasing the susceptibility to ballooning and rupture of the aorta. Huei-Hsin Clarice Yang is studying the effect of Marfan syndrome on endothelial and smooth muscle cells in the aorta and the small arteries. She is expanding on previous research that found that smooth muscle in the Marfan-affected aortas is unable to relax normally. Her work focuses on the mechanisms that contribute to this dysfunction within smooth muscle cells and in the epilethial cells that regulate vascular contraction and relaxation. Yang’s work will provide valuable insight into how Marfan syndrome causes decreased contracting and relaxing abilities of the arteries. Ultimately, this knowledge could lead to innovative therapies to prevent or treat aortic rupture and to halt the vascular deterioration process in patients with Marfan syndrome

The impact of therapeutic design on social engagement among residents with dementia during programmed activities in dementia care units

Dementia special care units (SCU) and freestanding special care facilities (SCF) for people with dementia are built using design principles that have been shown to enhance quality of life and reduce responsive behaviours that often occur when residents are disoriented or overstimulated by their surroundings. More supportive environments in these facilities are created through smaller unit sizes, homelike ambience, increased wayfinding, smaller activity spaces, and access to safe and secure wandering paths. Architectural planning and design features can improve the physical context where programmed activities such as music therapy, exercise sessions, creative arts, and therapy gardening occur. However, these specially designed spaces offer few therapeutic benefits without appropriate staff resources and family involvement to make the programs succeed, and consideration must be given to the combined effects of physical design, programs and policies, and staffing issues. Few studies have systematically assessed how modifications to the physical environment work in concert with social and organizational factors to enhance opportunities for residents to engage in positive social interactions through meaningful programmed activities. Krista Frazee is exploring the impact of the physical and social environments of care settings on residents’ social engagement during programmed activities in SCUs and SCFs, versus traditional integrated care facilities. She will also assess staff and family caregiver perceptions of activity spaces in helping them provide meaningful planned activities for residents. The findings from this study will be used to inform architects, interior designers, facility administrators and staff in various ways they can support the care and quality of life of residents with dementia through the integration of physical design and programmed activities.

CD34 in development of lung inflammatory diseases

Ever since its discovery more than 20 years ago, the CD34 antigen has been widely used as a marker to identify stem cells, precursor cells that give rise to all types of specialized cells. However, the exact function of CD34 expression on hematopoietic precursors and mature cells is still not well understood. Dr. Marie-Renée Blanchet and colleagues have uncovered some fascinating details about the role of CD34 in allergy and asthma. The team recently demonstrated that CD34 is expressed on mature mast cells and eosinophils – two types of cell that respond to injury during inflammation of the body’s tissues – and that the CD34 antigen is involved in their recruitment to the lung and peritoneum. They showed that mice without the CD34 antigen are protected against development of airway hyper-responsiveness and airway inflammation, which are two major hallmarks of allergic asthma. Finally, in preliminary experiments, these mice also showed protection in hypersensitivity pneumonitis, another model of lung inflammation. Now, Blanchet is working to better understand the mechanisms behind these recent findings. Many cell types involved in asthma and hypersensitivity pneumonitis express CD34, some in which the role of this protein remains unknown (eg. fibrocytes and dendritic cells). She plans to use models to elucidate the role of CD34 expression in these cells. Ultimately, she hopes her studies will reveal potential targets for treatment of allergy and inflammation.

Analysis of gene function in the specification of jaw identity

The genetic basis of many facial defects remains unclear. One of the reasons is that we only have a partial picture of gene expression during facial development – when, and in what sequence, particular genes are turned on and off to give rise to the bones, nerves and muscles of the face. This enables the same tissues, which are used in all parts of the face, to arrange themselves in particular patterns to create to a fully-formed face. Dr. Suresh Nimmagadda focuses on how the lower and upper jaws are formed during embryonic development, arising from tiny buds of tissue surrounding the mouth. In particular, he is studying retinoic acid (RA) and bone morphogenetic proteins (BMP), which are secreted during development. He hopes to reveal the roles played by gene targets of BMP and RA in establishing jaw identity. The long term goal of his research is to improve our understanding of the normal and abnormal facial development, forming the basis for new ways to prevent facial defects.

Examining the interplay between adherence and antiretroviral treatment on disease outcomes over time in HIV/AIDS-infected patients

HIV therapy has evolved tremendously due to the development of new drugs, new technologies to measure viral response and drug resistance, and an improved understanding of how the virus progresses in the body. Modern highly active antiretroviral therapies (HAART) suppress the amount of virus circulating in the blood to nearly undetectable levels for long periods, enabling the immune system to rebound, reducing HIV drug resistance and preventing this otherwise fatal disease from progressing. Clinicians have identified that many people on HAART therapies do not fully adhere to the prescribed therapy, and that their level of adherence typically changes over time. This lack of adherence is known to increase the risk of illness and death, but the specifics remain unclear. More information is needed to determine how adherence dynamically affects disease progression and outcomes, so those at higher risk of treatment failure can be identified in advance and helped with their treatment. Dr. Viviane Lima is exploring the relationship between regimen-specific adherence for key HAART therapies and the disease outcomes for patients. She will determine the levels of adherence required at each stage to reduce or prevent a number of disease outcomes: viral rebound, immune cell loss, HIV drug resistance, the emergence of AIDS-related conditions, and death. She hypothesizes that for each disease outcome, there is a distinct, clinically-significant interaction between adherence and type of HAART therapy. Long-term management of HIV/AIDS requires a long-term commitment from patients to adhere to therapy, a high level of expertise among practitioners to deal with complex and rapidly evolving treatments, and the development of clinically meaningful tools to enhance adherence over time and across varied treatments. Lima’s study will provide an evidence base to identify best treatment practices.

The development and application of algorithms for interpreting next-generation Solexa sequencing data: creation of a genome-wide breast cancer mutation map

Breast cancer is the most common malignancy in North American women, with more than 20,000 new cases diagnosed each year in Canada. Promising new treatments like Herceptin take advantage of genetic changes that occur in breast cancer cells, which can be detected by assessing specific tumour biomarkers. This approach is possible thanks to the successful sequencing of the human genome and the development of faster, cheaper sequencing technologies. One such technology is the Illumina 1G, a sequencing platform that can sequence a full genome for medical purposes in a matter of weeks. However, this new technology requires the development of new methods for the analysis and interpretation of the output. Anthony Fejes is demonstrating the utility of these new sequencing technologies by applying them to the study of breast cancer. By fully sequencing the genome of breast cancer-derived cell lines, he will create a genetic “map” that identifies the location and nature of the changes underlying the transformation of healthy cells into cancer cells. He will then validate the maps by identifying specific genetic errors that contribute to the development of cancer, and attempt to identify currently available drugs that can be re-purposed to target these broken cellular elements. This combination of sequencing, computational analysis, and drug candidate testing provides a single “”genome-to-therapeutic”” work flow, demonstrating a method that can be applied to the development of personalized medicines. Fejes’ research will also allow researchers to find new approaches to the treatment of cancers, through development of a technique that can be applied to other genetic disorders.

Biological role of IL-7Ralpha Y449-dependent and -independent signals in T cell development and function

The molecule interleukin-7 (IL-7) is an important regulator of the development and signalling function of T cells, the white blood cells involved in fighting off infection and coordinating an efficient immune response. Loss of IL-7 signalling in humans results in a complete lack of T cells, demonstrating the necessity of IL-7 in the development of these important cells. After T cells mature, they circulate through the blood, searching out invading pathogens, mounting an immune response and clearing the infection. This process generates specialized memory T cells, which are able to mount a stronger and more efficient immune response upon subsequent encounters with the same pathogen. Memory cell development is the basis of vaccination, which serves to “prime” the immune system to ward off infections. Growing evidence indicates that not only is IL-7 essential in the development of these memory T cells, but that its overproduction is also implicated in a number of immune system cancers. Lisa Osborne was previously funded by MSFHR for her early PhD research training. She is now continuing her studies of IL-7. Using a number of genetic models of IL-7 signalling, Osborne will clarify the IL-7 mediated biochemical pathways that are involved in a number of T cell processes. She aims to demonstrate which molecule or pathway is primarily involved in the de-regulated growth of T cells that leads to cancer. Ultimately, this research could guide the development of vaccines that rely on the generation of memory T cells against a particular pathogen. Her work will also provide insights into the development of immune system cancers, and potentially a novel treatment approach.

Neurophysiological markers of the control and deployment of attention in healthy individuals and individuals with attentional deficits

In order to successfully interact with the world around us, we need to be able to focus our attention on a particular object or location, move our attentional focus from one location to another, and suppress distracting information. A number of areas of the brain have been identified as part of a network of brain regions that work together to accomplish these complex cognitive processes, but there is still very little known about how these brain areas work together to control attention. A number of neuropsychological disorders, including attention deficit hyperactivity disorder (ADHD), dyslexia, schizophrenia, and depression are accompanied by deficits in the ability to focus attention and suppress distracting information in the environment. These deficits appear to originate from different underlying causes within the overall network of brain regions responsible for attention. Jessica Green is working to identify the brain areas responsible for our ability to pay attention, and determining how these brain areas interact in healthy individuals. She will then use this baseline knowledge to explore the neural basis of attentional deficits. Using electroencephalography (EEG), Green is capitalizing on recently-developed techniques for localizing the neural sources of the EEG. She will determine not only which brain areas are involved in shifting our attention between locations in space, but also how the activity changes over time as these brain areas interact with one another. In particular, she seeks to determine whether dyslexia arises from changes in attentional processing and, if so, which brain areas and connections between brain areas are affected. A better understanding of the neural basis of attentional deficits will potentially aid in the more efficient and appropriate diagnosis and treatment of these deficits.

An investigation of the impact of crystal methamphetamine use on sexual and injection-related risk behaviour among street youth and injection drug users in Vancouver

Illicit drug use is a major public health concern in British Columbia, most notably the high rates of HIV and Hepatitis C transmission among injection drug users. Additionally, in Vancouver and elsewhere in British Columbia, there is concern regarding escalating rates of crystal methamphetamine (CM) use. The prevalence of CM use is rising internationally, and has been associated with unsafe sexual and injecting practices among specific subpopulations at risk for HIV. However, the potential associations between CM use and sexual and injection-related risk behaviour among marginalized populations in Vancouver have not been thoroughly investigated. Brandon Marshall was previously funded by MSFHR for his Master’s work studying the interactions between drug use and sexual risk behaviour among street youth in Vancouver. He is now continuing his examination of a number of social, environmental, and structural factors that predict frequent CM use and subsequent health-related harms among young injection drug users. He hypothesizes that social disadvantage, impoverished living conditions, frequent exposure to law enforcement, and poor access to health and harm reduction services will be associated with higher frequency and intensity of CM use. This research will help inform evidence-based public health policy and interventions for marginalized populations. Marshall’s findings may be used to develop strategies that seek to reduce the harms associated with CM use, prevent further transmission of HIV and Hepatitis C, and provide better support for youth and injection drug users who are already infected.