Functional characterization of the chorea-acanthocytosis gene VPS13A in the yeast Saccharomyces cerevisiae

Many diseases such as cancer, atherosclerosis (narrowing and hardening of the arteries) and neurodegenerative disorders stem from problems with the uptake, transportation, storage and recycling of molecules. Proper sorting is necessary for normal cell function since many molecules are only required in specific areas or compartments of the cell. In the case of neurodegenerative disorders, defective protein sorting in nerve cells can lead to brain tissue deterioration. Disease caused by abnormal protein sorting can be studied in very simple organisms such as yeast, and the findings directly applied to human cells. Dr. Leslie Grad is researching a yeast protein, Vps13, which is very similar to a protein encoded by the human gene VPS13A. Defects in this gene can lead to chorea acanthocytosis, a neurodegenerative disorder associated with abnormal red blood cells, epilepsy, and muscle and nerve cell degradation leading to premature death. The findings could provide insight into the complicated mechanisms that regulate sorting of molecules inside cells and explain the molecular function of Vps13. Ultimately, Dr. Grad hopes to apply his findings to human cells and contribute to the development of therapies for neurological disorders caused by abnormal protein sorting.

Molecular mechanisms of retrograde transport

A single human cell is made up of many small organelles (compartments). Through a process known as vesicle transport, proteins and lipids move from one compartment to another to support and maintain cell function. Motor nerve cell diseases are progressive disorders involving the nerve cells responsible for carrying impulses that instruct the muscles in the upper and lower body to move. Abnormal vesicle transport causes a family of these devastating diseases, including Lou Gehrig’s disease (Amyotrophic Lateral Sclerosis or ALS). Abnormal vesicle transport has also been found in Alzheimer’s, Down syndrome, and Neimann-Pick C disease, suggesting that these abnormalities also play a role in the development of these diseases. To better understand these diseases and hopefully lead to improved treatments, Dr. Benjamen Montpetit is focusing his research on determining how vesicle transport works. Montpetit, who received MSFHR trainee awards in 2002 and 2006 in support of his PhD research, is studying the process in yeast with the aid of robotic-based systems. Yeast makes an excellent model for his research because the yeast genome has been fully sequenced and, therefore, its genetic code is known.

Safety of home birth: Consequences of hemorrhage in home birth

The safety of home birth for women at no identifiable risk is a controversial issue. Approximately 40 per cent of women accessing midwives in BC choose to give birth at home. If there is an emergency related to birth, access to definitive care can be delayed by geography, weather and timing of labour. Severe hemorrhage (bleeding) during childbirth is a clinical emergency that requires immediate invasive interventions by specialized health professionals. It is one of the top three leading causes of death among mothers. Survivors are at risk of developing kidney damage, surgical removal of the uterus and adverse events associated with blood transfusions. But little is known about the consequences of hemorrhage in home birth. Eman Hassan is researching the risk of developing serious consequences following hemorrhage in the home birth setting. She is comparing rates of unfavourable events that occurred due to hemorrhage among planned home births and planned hospital births in the period 2002-2004. The study will provide important information to practicing midwives and childbearing women about what may contribute to hemorrhage, who is at greater risk of developing these events, and the factors that may affect timely access to specialized care. This information will help prevent serious health problems among women considering home birth in BC, and will also be applicable to other provinces in Canada.

The MTHFR C677T polymorphism and postpartum mental illness in at-risk women

Psychotic disorders (which include schizophrenia, schizoaffective and bipolar disorders) are common mental illnesses, affecting about 3 per cent of the population. Women face a number of challenges when dealing with these disorders, especially when it comes to pregnancy, childbirth and parenting. Women with a history of a psychotic disorder have substantial risks for a postpartum episode of mental illness like depression or psychosis. Postpartum mental illness carries risks for suicide and infanticide, as well as other less dramatic but still significant problems like difficulties with parenting skills and problems with mother-child bonding and attachment. Research has shown that, in general, psychotic disorders stem from interactions between genetic and environmental influences. The specific genetic variations that increase risk for postpartum episodes of mental illness are largely unknown. Dr. Jehannine Austin will use a new approach to investigate whether a variation to one particular gene contributes to risk for postpartum episodes of mental illness in women with a history of mental illness. This gene is known to encode a protein whose function is dependant on the B vitamin, folate. Dr. Austin will not only look at genetic variations, but will also measure folate levels in pregnant women at high risk of postpartum mental illness. If her work shows that the genetic variation plays a role in risk for postpartum mental illness, it may be possible to decrease risk for postpartum episodes of mental illness by providing folate supplements for these women.

Characterizing the role of palmitoylation in the trafficking of multispanning membrane proteins to the cell surface

Molecules are transported to various parts inside the cell to maintain vital functions, such as cell growth and communication. For example, many proteins regulate the intake of nutrients or detect external signals — it’s crucial to cell survival that these proteins are transported to the cell surface so the cells can recognize and respond appropriately to the different stimuli they encounter. However, there is much to be learned about the way these proteins are transported. This is the focus of Karen Lam’s research, in particular, understanding the mechanisms by which the saturated fatty acid palmitate attaches to proteins (I do not work with brain cells, but with yeast cells, which serve as a model) and affects their transport to the cell surface. For example, palmitate attaches to various proteins found in brain cells. Many of these proteins help chemicals called neurotransmitters send signals in the brain, a process that’s essential for learning and memory. Defects in this communication can result in neurological diseases like Alzheimer, Huntington and Parkinson’s. Lam wants to determine what causes defective function and transport in these proteins by modeling the processes in yeast cells. Understanding the fundamental mechanisms of palmitate attachment may lead to the development of molecular-based therapies to treat a variety of neurological disorders.

Use of the skin immune system and dendritic cells to alter systemic immunity

The skin is the largest organ of the human body and represents the body’s primary interface with the external environment. As such, the skin is challenged by a broad range of factors and conditions. These include both endogenous (genetic, immunologic, and systemic) and exogenous (solar radiation, allergens, irritants, pollutants, and microbes) factors. As a result, the skin is a major site for disease including inflammation and cancer. Dendritic cells are immune cells that begin and coordinate immune responses. The skin is one of the largest repositories of these dendritic cells. Thus, in addition to being a direct target for inflammation, the skin is one of the prime sites where systemic immune responses begin. The proposed program includes four primary themes. The first three themes revolve around the use of the skin immune system (and skin dendritic cells) to modify immune responses (The skin immune system in the induction of immune responses; The skin immune system in the reduction of immune responses and; The skin immune system in disease pathogenesis). The final theme involves the use of pharmaceutical agents to modulate the activity of nonskin derived dendritic cells. The skin offers a unique opportunity to observe and manipulate dendritic cells and thereby the immune system. The focus on the skin as an organ to manipulate immune responses is innovative. This program will lead to a better understanding of the role of the skin immune system in systemic as well as local autoimmune disease (examples include lupus, psoriasis and type 1 diabetes). Further, the program will lead to cost effective strategies to treat and prevent human disease with anticipated improvements in vaccine delivery and efficacy and novel methods to control autoimmune disease.

Mechanisms of topical calcipotriol mediated tolerance induction

Autoimmune diseases such as type 1 diabetes, lupus, and multiple sclerosis are a serious health issue in North America, affecting more than 22 million people in the US alone. Unfortunately, current treatment options for individuals suffering from autoimmunity are limited, and patients are often faced with the prospect of life-long drug regimens designed to suppress their immune systems. While effectively managing autoimmune diseases, these drugs can also hamper the body’s ability to defend itself against infection and cancer, substantially reducing a patient’s quality of life. T regulatory cells (Tregs) are a class of immune cell that prevent the immune system from attacking the body. Because Tregs can prevent autoimmune disease, many attempts have been made at designing methods to generate them. As of yet, no practical and reliable means of producing Tregs has been achieved. Previous research demonstrates that Vitamin D may play a role in the Treg production process. Paxton Bach is investigating whether applying Vitamin D to the skin can be used to generate Tregs, and early results are promising. Ultimately, this research could lead to more effective, less invasive treatments for individuals living with autoimmune diseases around the world.

Characterization of retrograde transport machinery and its relationship to amyotrophic lateral sclerosis (ALS) using the yeast model system

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a rapidly progressive motor neuron disease that causes paralysis and is ultimately fatal. In ALS, motor neurons (nerve cells) are impaired and eventually die. This process breaks the connection between voluntary muscles, which individuals control, and the brain. Other types of brain cells are unaffected, which means patients become paralyzed but their cognitive abilities remain intact. Specialized transport proteins carry survival signals from one end of the neuron to the other. In a mouse model of ALS, the cause of motor neuron disease was found to be due to a mutation in the Vps54 transport protein. In all types of cells, material is transported in a specialized container called a vesicle. In her research, Nicole Quenneville has found that a particular region of the Vps54 transport protein is involved in recognizing the surface of vesicles. It’s this region that is mutated in the mouse model of ALS, suggesting that faulty recognition and transport of these vesicles may lead to motor neuron disease. Using a yeast model, Quenneville is further investigating whether the Vps54 mutation causes transport defects, and whether the mutation changes the interactions that the Vps54 protein has with other proteins. As well, she aims to identify genes and proteins that work with Vps54 to transport molecules within the cell. Quenneville hopes her research will help identify candidate genes for novel therapies, diagnosis, and assessment of susceptibility to ALS.

Wild-type Huntingtin’s pro-survival function: A potential role in Huntington’s disease pathogenesis and treatment

Huntington's Disease (HD) is an Inherited brain disorder affecting approximately 1 in 10,000 Canadians that causes progressive disability with an inexorable march towards death averaging 18 years after the onset of symptoms. There is currently no cure for HD and no known treatment that affects the age of onset or the progression of symptoms. The underlying genetic defect that causes HD is now known and the mutant HD gene produces an abnormal protein called huntingtin (htt) that damages brain cells. Many research groups around the world are studying how the abnormal htt protein kills cells, but the normal cellular function of htt is not well understood. This proposal is unique in that we will examine the protective role that the normal htt protein may play in the disease process of HD. We previously demonstrated that the normal htt protein has a pro-survival function in the brain and prevents various forms of brain cell death. Our proposed experiments will determine what specific regions of htt are required for this protective role, how protein modifications of htt affect this function, and we will test what effect modulating levels of normal htt have on the progression and development of HD. Based on our preliminary results, I hypothesize that altering the pro-survival function of htt will modulate the process of brain cell injury in HD. Mapping the critical pro-survival regions of htt, investigating the mechanisms by which this function is regulated, and understanding the downstream pathways by which htt modulates brain cell death may provide novel cellular therapeutic targets for HD and for neurodegenerative disorders in general.

The role of imprinting in placentation and obstetrical complications

Up to one per cent of pregnancies in British Columbia end in stillbirth. Two conditions thought to contribute to the rate of stillbirths are pre-eclampsia and intrauterine growth restriction (IUGR). Pre-eclampsia – a form of pregnancy-induced high blood pressure – affects approximately five per cent of pregnancies, and can be life-threatening to both mother and fetus. IUGR – where the fetus is significantly undersized for its gestational age – also affects approximately five per cent of pregnancies, and is linked to health problems at birth and beyond. Abnormal placental development is thought to be responsible for many complications of pregnancy, including pre-eclampsia and IUGR. The causes underlying abnormal placental development are largely unknown. It may involve errors in DNA methylation, a mechanism used to regulate the activity of certain genes – particularly imprinted genes. Unlike the more common type of genetic inheritance where the outcome in the offspring will depend on whether a gene is dominant or recessive, imprinted genes are parent-of-origin-specific, meaning they are only expressed from either the maternal or paternal chromosome. The placenta has an overabundance of genes expressed in this way. Errors in DNA methylation and imprinting can result in changes in gene expression. Danielle Bourque’s project aims to determine if disruption of normal DNA methylation and imprinted gene expression leads to the abnormal placental development associated with pre-eclampsia or IUGR. The eventual goal is to develop a strategy to improve early diagnosis of pre-eclampsia and IUGR, which will lead to improved treatments and outcomes for both mother and baby.