Epigenetic mechanisms regulating the acquisition and extinction of conditioned fear: exploring the neurobiology of relapse

A major obstacle in the treatment of fear-related anxiety disorders is their likelihood for relapse. Fear-related behaviour can be inhibited with extinction therapy (repeated exposure to specific fear-inducing cues). This is, however, a temporary fix because fear often returns after exposure to cues associated with the original learning. In the case of post-traumatic stress disorder, fear can also “incubate” or sensitize over time and further exacerbating symptoms of the disorder. These phenomena likely reflect long-term neural adaptation that occurs during learning – changes that may be based on lasting epigenetic modification of genes responsible for maintaining fear memories. Epigenetic modifications influence the way a gene functions without altering the underlying DNA sequence- processes now recognized to participate in the regulation of gene expression in the adult brain. Rapidly emerging evidence suggests that epigenetic mechanisms play an important role in psychiatric disease and in disorders of learning and memory. Dr. Timothy Bredy is employing state-of-the-art technologies to investigate the fundamental epigenetic mechanisms of associative fear memory. He is using a genome-wide approach to examine epigenetic machinery involved in regulating critical gene targets during the acquisition and extinction of conditioned fear. Dr. Bredy hopes his findings will provide insight into the molecular basis of relapse and its prevention and that this research will ultimately contribute to the design of novel pharmacotherapeutic treatment approaches for fear-related anxiety disorders.

Pharmacogenomics of anthracycline-induced cardiotoxicity in childhood

Serious adverse drug reactions (ADRs) are the fourth leading cause of death and illness in the developed world, claiming many lives and costing billions of dollars each year. Children are especially at risk for ADRs: an estimated 15 per cent of all children admitted to hospitals get ADRs. Although many factors influence the effect of drugs, such as age, weight and organ function, genetic factors account for a great proportion. Small genetic differences between patients can cause serious ADRs. One group of drugs, called anthracyclines, are an effective treatment for many children and adults with cancer. However, they can sometimes be very harmful or damaging to the heart (cardiotoxicity), resulting in life-long drug treatment, the need for heart transplantation, or death. Dr. Henk Visscher is working to find the genetic factors behind this phenomenon. He is comparing gene variants between children who have experienced severe cardiotoxicity after receiving anthracyclines with children who did not. Using high-tech machines, he can screen for thousands of gene variants at the same time, making it more likely to find the gene(s) involved. Once identified, he will conduct a number of studies to confirm that the identified gene variants are the “culprits.” Visscher plans to create a diagnostic test based on the variants that can predict cardiotoxicity in patients taking anthracyclines. This would enable physicians to identify at-risk patients before they take the drugs, allowing them to adjust the dose, choose a different drug or monitor a high-risk patient more closely. Ultimately, this may help prevent potentially fatal heart disease among cancer survivors.

British Columbia Burden of Injury

Injuries are a significant public health problem in BC. Every year about 1,600 British Columbians die due to injury, 42,000 are hospitalized, and an estimated 400,000 people throughout the province sustain some sort of injury. The cumulative effect of injury on a population is known as the burden of injury. Burden of injury data help policy makers and practitioners determine the effectiveness of current services in injury prevention and injury treatment, and provide direction about new interventions that would have the greatest impact. They also help provide estimates for recovery time across different injuries. However, very little is known about the burden of injury, making this an important priority for research.

Dr. Mariana Brussoni is leading a longitudinal study in BC to quantify the impacts of injury on individuals and on the health system. Drawing on her experience working in England with international experts in injury research and prevention, Brussoni is recruiting more than 1,400 injured people of all ages across urban and rural settings in BC. They will be followed for 12 months post-injury, with the research team tracking their quality of life and recovery, use of health and social services, and time away from school or work. The goal of this research is to more fully describe the various impacts of injury in British Columbia, and to identify areas where prevention and treatment interventions could make the biggest difference.

YB-1 induction of PIK3CA mediates herceptin resistance in Breast Cancer patients

Breast cancer accounts for more than 30 per cent of all new cancer cases in Canada. One in nine women will be diagnosed with breast cancer in their lifetime, while one in 27 will die of the disease. This translates to 23,000 new diagnoses and 5,300 deaths in Canada every year. An aggressive form of breast cancer is called the Her-2 subtype. These tumours produce a protein called Her-2, which helps the cells grow uncontrollably. The drug Herceptin acts against the Her-2 protein. While this drug is effective, there are limitations to Herceptin’s usefulness since many patients develop resistance to the drug. Recent research has uncovered a protein called Y-box binding protein-1 (YB-1), which is expressed (produced) at high levels in the Her-2 subtype of breast cancer. While the YB-1 protein is not found in normal cells, it is found in 66.4 per cent of Her-2 subtype breast cancers. This makes YB-1 an attractive target for treatment, as inhibiting it will not affect normal cells. The protein promotes tumour growth by altering the levels of other tumour-enhancing proteins, such as PI3K. Arezoo Astanehe is investigating whether the increase in PI3K by YB-1 is one reason that cells become resistant to the effects of Herceptin. She hypothesizes that by inhibiting YB-1 and PI3K expression, Her-2 cancer cells would remain sensitive to Herceptin. Astanehe’s findings could identify new drug targets to help prevent Herceptin resistance and increase long-term survival of women with this aggressive and deadly form of breast cancer.

Genomic neighborhoods and inherited disease: the case for SIOD

While completing medical training in clinical genetics, Dr. Cornelius Boerkoel was consulted on two patients with a rare disease called Schimke immuno-osseous dysplasia (SIOD). At the time, there was little known about the disease, other than that it involved kidney failure and abnormal bone growth causing short height. Dr. Boerkoel’s early research in this area highlighted several previously unknown features of this disease, including the cause of SIOD: mutations (alterations) in both copies of a gene named SMARCAL1. He has also shown that SIOD arises from abnormal activity across most genes. Working with fly and mouse models that he developed to study SIOD, Dr. Boerkoel has created a model for studying how many small alterations in gene expression can cause disease.

Since common diseases such as atherosclerosis, stroke, endocrine dysfunction, immunodeficiency, and poor growth are all features of SIOD, this research is relevant to a better understanding of various unstudied mechanisms underlying these common diseases in the general population. To continue this work, Dr. Boerkoel will complete characterization of the function of SMARCAL1 using biochemical, fruit fly and mouse studies. He will test whether hormone supplementation might be an effective treatment for SIOD. Dr. Boerkoel will also determine whether the gene expression changes observed in SIOD are a feature in other patient populations affected with diseases also found in SIOD. This research will develop a new and unique model for understanding how changes in gene expression can predispose individuals to disease.

Regulation of intestinal homeostasis by colonic goblet cells in response to commensal and pathogenic bacteria

The gut lumen (interior space of the intestine) has developed to live in harmony with trillions of bacteria, many of which are beneficial to human health by helping in digestion and making vitamins. However, this harmony can be broken if the bacteria start to enter body tissues instead of staying in the lumenal space. Preventing this is the lining of the gut surface, which is made up of a single layer of different cells, including goblet cells. Goblet cells are single-celled mucus factories, specialized to make molecules that form a layer of mucus over the intestinal wall. While the mucus layer is believed to have a protective role, its function is not well studied in people. However, animal models that that lack mucus in the gut develop unwanted inflammatory responses and even cancer, suggesting an important function for this layer. Furthermore, defective mucus production is seen in patients with inflammatory bowel disease (IBD), which is characterized by excessive immune responses to our normally friendly bacteria. Previously funded by an MSFHR Junior Graduate Studentship award, Kirk Bergstrom is continuing his studies on how mucus-producing goblet cells promote healthy interactions with beneficial bacteria in the gut, and how they defend against harmful bacteria. He is using animal models of bacterial-driven gut inflammation, including an infection model that copies human disease. Bergstrom’s studies will shed light on how goblet cells help maintain this delicate balance within the gut. Also, since mucus production by goblet cells can be controlled by certain foods, these studies could lead the way toward new, noninvasive therapies based on nutrition to treat patients suffering from bacterial infections of the gut, or IBD.

Extraction and evaluation of transcription factor gene-disease association

Genes are the basic blueprints used by the cells in our body. When a gene is modified, the cells in our body can be affected; in the worst case, this can cause a disease. A researcher can often be faced with several candidate genes to study in relation to a particular disease, and choosing the genes with the best potential for discovery is important for making the best use of research resources. Around the world, researchers are studying thousands of different genes to understand their roles in health and disease states. Their findings – in the form of abstracts and annotations – are captured in a variety of databases. However, this vast source of biomedical literature is an under-utilized resource. Powerful computational biology methods are required to allow researchers to mine this information. Warren Cheung is developing an automated system that can examine the available biomedical literature and quantitatively determine which genes are most likely involved in a particular disease. Not only will the system identify previous relevant findings, its integration of data and annotations from many studies is expected to identify previously unknown associations between genes and diseases. Cheung’s research will initially focus on the involvement of transcription factor genes in brain diseases and cancer. However, the techniques developed and tested will be easily adaptable to all types of genes and diseases. Cheung’s award is jointly funded by MSFHR and the Down Syndrome Research Foundation. With the ability to automatically look at all the papers that have been published on genes and their functions, this system will make unbiased predictions and previously unknown linkages. This promises to be a powerful tool for understanding genes and disease.

Aging-induced changes in microdomains of vascular smooth muscle lead to alterations in vasomotor function

Cardiovascular diseases are the primary cause of death and disability in Canada, accounting for one-third of all deaths in 2002. Age significantly increases the risk of developing cardiovascular diseases. As our elderly population increases, it is very important to improve our understanding of how and why cardiovascular diseases occur with age. Most cardiovascular diseases are caused by problems with the way our blood vessels work, especially changes in the muscle layer (made of cells called smooth muscle) that surrounds the blood vessels. The calcium level in smooth muscle is critical for proper cell function, allowing the muscles to contract and generate force. Within the cell, the way that internal compartments called organelles are arranged in relation to each other allows high concentrations of calcium to be localized to small pockets of the cell called microdomains. Microdomains are important for smooth muscle cells to function properly, because certain adjacent proteins are only activated by high concentrations of calcium. Disintegration of microdomains leads to the development of various health conditions. Harley Syyong was previously funded by MSFHR for his Master’s research training. He hypothesizes that smooth muscle cells undergo major changes in organelle arrangement as we age – making it difficult or impossible for cells to form calcium microdomains. Furthermore, proteins that generate microdomains may also be affected, including changes in where they are located or how much of the protein is made. Syyong is monitoring different blood vessels across time, identifying changes to organelles and proteins and determining how they affect blood vessel function. He hopes a better understanding of these changes could lead to ways to decrease the effects of aging on blood vessels, alleviating cardiovascular disease in the growing older population.

The role of Chlamydia pneumoniae and cytomegalovirus in preeclampsia: a link between preeclampsia and later atherosclerosis

Preeclampsia is the most common dangerous complication of pregnancy, affecting the health of both mother and fetus. While high blood pressure in the mother and the excretion of protein in her urine are the most visible symptoms of the disease, preeclampsia also causes systemic inflammation and organ damage. When this disorder occurs early in pregnancy, it is particularly dangerous and increases a woman’s later cardiovascular risk. Normally during pregnancy, the immune system changes and women become more susceptible to infectious agents. Two infectious agents in particular, Chlamydia pneumoniae (a bacteria) and cytomegalovirus (a virus), are thought to trigger early onset preeclampsia. These agents have already been linked to the development of cardiovascular disease later in life. However, it is still unclear what role they play in the onset and development of preeclampsia and its long term cardiovascular effects. Fang Xie is investigating the mechanisms between infection, innate immune response and the development of preeclampsia. Focusing on Chlamydia pneumoniae and cytomegalovirus, she will determine how pregnant women are affected by these two infectious agents and how immune system receptors respond to the infection, including possible gene mutations and inflammatory changes associated with these two types of agents. She will also determine whether infection results in changes to blood clotting mechanisms during pregnancy. A greater understanding of the role of infectious agents in preeclampsia will help in developing targeted treatments to prevent and cure this disease, leading to improved health care for both mother and fetus.

A novel role for nuclear EGFR in breast cancer progression and therapeutic resistance

Breast cancer is a major public health problem worldwide. In the United States alone, 178,480 new cases of breast cancer and 40,910 breast cancer deaths were expected in 2007. This unequivocally makes breast cancer the most common cancer in Western women, and second only to lung cancer in terms of cancer morbidity. Alarmingly, the incidence of breast cancer continues to rise with enormous physical, psychological, and social effects on the women who are faced with cancer diagnosis and treatment. During the last decade, great strides have been made in reducing breast cancer morbidity through increased mammography screening coupled with the advent of multi-agent chemotherapy and Tamoxifen. However, treatment of basal-like breast cancer (BLBC) remains especially challenging as these tumours lack the estrogen, progesterone, and HER2 receptors targeted by many traditional chemotherapeutic drugs. Moreover, the tumours readily develop resistance to new generation chemotherapeutic agents, such as Iressa. Further studies are desperately needed to uncover novel signalling cascades responsible for cancer progression that could ultimately be manipulated to combat this highly aggressive subset of breast cancer. The surface of cells are coated with receptors that “listen” to cues from the surrounding environment to direct cells to proliferate, synthesize and excrete proteins, or even undergo apoptosis (cell death). Traditionally, it was believed that these signals were sent to the cell nucleus exclusively through complex and elaborate cascades of intracellular messengers. However, it has recently emerged that cell receptors can become internalized and trafficked to the nucleus where they can act as transcription factors – in essence proteins that can turn on and off particular genes. This novel pathway has tremendous consequences for cancer biology as it offers a novel mechanism which cancerous cells could be exploiting to proliferate, metastasize (spread to other sites), to even combat the effects of chemotherapy. I have recently demonstrated that a fragment of the epidermal growth factor receptor (EGFR) translocates from the cell surface to the nucleus in BLBC cells. This is an exciting finding because EGFR is overexpressed in 50% of BLBCs, but more importantly, it could explain why these cells are resistant to Iressa, a chemotherapeutic that inhibits EGFR from sending messages via signal transduction cascades. Specifically, a fragment of the receptor could be cleaved to directly activate pro-survival genes in the nucleus. My research proposal is focused on gaining a more in depth understanding of this novel, cleaved form of EGFR, known as nuclear EGFR. Specifically, I am interested in determining the structure of nuclear EGFR and uncovering if it interacts with other proteins in the nucleus. In addition, I want to discover the specific pro-survival genes that are being induced by nuclear EGFR. This work will determine if targeting nuclear EGFR represents a viable strategy for combating cell proliferation, metastasis, and therapeutic resistance in a subset of cancer where treatment options are currently limited.