Fall 2017

The seminars are held on Wednesdays at 12:30pm in the lecture room GB03 in wing B

(Click on the green bar to find out more about the speaker and the topic)

September 20, 2017 - Dr. Michael Levin Univ. of Saskatchewan

The long-term goal of research in the LEVIN LAB is to better understand the cause of neurodegeneration, a salient feature and cause of permanent disability in progressive multiple sclerosis (MS) patients. For more than 20 years, we have studied the function of the RNA binding protein heterogeneous nuclear ribonuclear protein A1 (hnRNP A1 -‘A1’), with a focus on ‘M9’. M9 is A1’s nucleocytoplasmic transport domain, and is required for transport of A1 between the nucleus and cytoplasm. Our lab has discovered that MS patients make antibodies to M9 and the brains and lymphocytes of MS patients contain somatic DNA mutations within M9. Using a number of molecular, in vitro and in vivo techniques, our data indicate that DNA mutations within M9 and autoimmunity to M9 result in A1 dysfunction and subsequent neuronal and axonal degeneration. In this presentation, we will examine potential mechanisms of neurodegeneration resulting from A1 dysfunction.

Michael C. Levin, M.D., is the inaugural SK Multiple Sclerosis Clinical Research Chair and Professor of Neurology & Anatomy-Cell Biology at the U of S. He received his Bachelors of Science degree in chemistry with special honors at the George Washington University and his medical degree at Pennsylvania State University. He attained basic neuroscience training at The Salk Institute. Dr. Levin completed his residency training in neurology at The New York Hospital/Cornell Medical Center – Memorial Sloan Kettering Cancer Center. Drs. Fred Plum and Jerry Posner mentored him during his residency including while he was chief neurology resident. He then completed his multiple sclerosis post-doctoral fellowship in the Neuroimmunology Branch at NIH.

Title: A dysfunctional RNA binding protein contributes to neurodegeneration in multiple sclerosis (MS)

September 27, 2017 - Dr. Vikram Misra, Univ. of Saskatchewan

Several viruses, that appear to cause no overt disease in their natural bat hosts, have spilled over into other mammals causing serious and often fatal disease. These include viruses that cause diseases such as SARS, MERS, Marburg, Ebola, Hendra, Nipah and porcine epidemic diarrhea. An overblown inflammatory response exacerbates the pathology in these diseases. While there are many studies on the interaction of these viruses with their spillover hosts or surrogate laboratory animals, there is little information on the relationship of these or similar viruses with their natural bat hosts. Our objective is to examine the apparently benign relationship between viruses and their natural bat hosts as well as the factors that upset this relationship leading to increased virus replication and, potentially, to spillover to other species. We have identified unique Corona and Herpes viruses that persistently infect most members of two Canadian bat species with no overt signs of illness or pathology. Secondary fungal infections, however, cause an increase in virus replication. We have also discovered that while both bat and human cells react to viral infection with an antiviral response, pro-inflammatory pathways are actively suppressed in bat cells. Our studies will not only provide fundamental information about virus-host relationships in these specialized mammals, but will also give clues about mitigating the serious consequences that often accompany viral spill-over from bats to humans and other species.

Title: Viral spill-over from bats to humans

October 4, 2017 - Dr. Afshin Raouf, Univ. of Manitoba



Title: Breast tumours induce fibroblast-derived TGFb suppression of progenitor pool in adjacent normal-like tissue

October 11, 2017 - Dr. Maya Shmulevitz, Univ. of Alberta

Reovirus is an enteric virus that is being repurposed into an oncolytic therapy because it prefers to replicate in transformed cells over normal cells. Given that reovirus evolved to thrive in its natural intestinal environment, we wondered what changes to virus and host are required for optimal virus infection in the tumor niche. To address this question, we exposed reovirus to mutagens and used directed evolution to isolate adaptations that favor virus replication in tumor cells.  The unbiased approach revealed several mutations that can promote distinct steps of reovirus replication in tumor cells and promote oncolysis in vivo. The first half of the seminar will discuss examples of virus adaptations that favor reovirus infection of tumor cells. In the second half of the seminar, we will then consider the effects of cellular factors released by tumor cells on extracellular reovirus. In the intestine, reovirus exploits enteric proteases to promote infectivity; but do tumor-associated proteases affect reovirus in positive or negative ways? To address this question, we exposed reovirus to tumor extracellular extracts, and discovered that breast cancer-associated proteases inactivate reovirus. Altogether we propose that oncolytic viruses would benefit from reshaping towards their specific therapeutic niche.

Title: Reshaping oncolytic virus for the tumor niche

October 18, 2017 - Dr. Miroslaw Cygler, Univ. of Saskatchewan

Iron-sulfur (Fe/S) clusters are essential protein cofactors crucial for many cellular functions including DNA maintenance, protein translation, and energy conversion. De novo Fe/S cluster synthesis in mitochondria occurs on the scaffold protein ISCU and requires cysteine desulfurase NFS1, ferredoxin, frataxin, and the eukaryote-specific small factors ISD11 and ACP (acyl carrier protein). Both the mechanism of Fe/S cluster synthesis and function of ISD11-ACP are poorly understood. I will present crystal structures of three different NFS1-ISD11-ACP-ISCU complexes, and describe SAXS analyses to define the 3D architecture of the complete mitochondrial Fe/S cluster biosynthetic complex. The structural and concomitant biochemical studies provide mechanistic insights into Fe/S cluster synthesis at the catalytic center defined by the active-site Cys of NFS1 and conserved Cys, Asp and His residues of ISCU. We further assign specific regulatory rather than catalytic roles to ISD11-ACP that link Fe/S cluster synthesis with mitochondrial lipid synthesis and cellular energy status.

Title: Structural and functional model of the core complex of the eukaryotic Fe/S cluster synthesis machinery

October 25, 2017 - Dr. Jack Gray, Univ. of Saskatchewan

Insects are one of nature’s ideal systems for understanding principles of how animals sense and interact with their environment. They possess tractable nervous systems that evoke and control robust, predictable behaviours. Using traditional and advanced recording techniques, researchers can address fundamental questions regarding sensory processing and coordination of motor outputs that underlie adaptive behaviours. The use of ubiquitous neurotransmitter systems that convey information throughout the insect’s neural circuits further allows us to address questions related to environmental toxicity and how low doses of pesticides affect neural function and behaviour. I will describe experiments in our lab that incorporate these aspects of insects as model systems to address multiple questions. We use the well-described locust flight system to study visual detection of approaching objects and how collision avoidance behaviours are produced. We also study how sub-lethal doses of a neonicotinoid insecticide disrupt visual motion detection an impair avoidance behaviour.

Title: Insights from a tiny mind: Fundamental and practical insect neurobiology

November 1, 2017 - Dr. Joseph Rubin, Univ. of Saskatchewan

Antimicrobial resistance is a serious threat to the future of antimicrobial chemotherapy, and negatively impacts the health of humans and animals. Although animals (companion, food and wildlife) are recognized as a potential source of resistant organisms, the magnitude of the negative impact of these bacteria on human health is controversial and often politicized. The emergence of resistance to the β-lactam antimicrobials among gram negative bacteria is presently one of our most pressing threats. In E. coli, resistance to the β-lactams most often results from the production of degradative enzymes, β-lactamases. Broad spectrum β-lactamases including the extended spectrum β-lactamases (ESBLs) are especially concerning due to their ability to degrade the 3rd generation cephalosporins (e.g. ceftriaxone).

Despite the impact of ESBL producing E. coli on human health (e.g. ESBL producing E. coli ST131 is a frequent cause of urinary tract infections in women), very few studies describing the presence of such genes in animals have been published in North America. In this presentation, I will give a summary of my research group’s efforts to address some of these important gaps in animals in Canada.

Title: The Pandemic Under Our Noses – ESBLs in E. coli Colonizing Animals

November 15, 2017 - Dr. Daniel Chen (Univ. of Saskatchewan)

Tissue engineering is an emerging field with the aim of producing ‘artificial’ tissue or organ substitutes that can grow with patients, ultimately providing a permanent solution to damaged tissues or organs. In tissue engineering, tissue scaffolds play a crucial role. A tissue scaffold is a three-dimensional (3D) structure made from biomaterials with a highly interconnected pore network or microstructure that is used to facilitate cell growth and transport of nutrients and wastes while degrading gradually itself. Fabrication of scaffolds has proven to be a challenging task. One important barrier is the inability to fabricate scaffolds with a microstructure and spatially-controlled distribution of cells that mimics the structure and cell organization in native tissues, and with both mechanical and biological properties appropriate for tissue engineering applications. Recently, the speaker’s research group has been active to pursue research on bio-fabrication scaffolds for various tissue engineering applications, including the repair of peripheral nerve injuries, spinal cord injuries, articular cartilage, and myocardial infarction. In this presentation, the speaker will report their recent work and achievements, and discuss the challenges and the opportunities in this emerging field. The promising of the use synchrotron–based imaging to track scaffold placement and success in living tissue will also be discussed.

Title: Bio-Fabrication of Scaffolds for Tissue Engineering Applications

November 22, 2017 - Dr. Deborah Anderson, Univ. of Saskatchewan

CREB3L1 is a stress-activated transcription factor that functions as a breast cancer metastasis suppressor by blocking the expression of many genes that contribute to cancer progression, angiogenesis and the movement of cancer cells away from the primary tumor. Our previous work has shown that CREB3L1 expression is low in metastatic breast cancers and that re-expression of CREB3L1 can block angiogenesis to cause tumor regression and prevent breast cancer metastasis. We are using two strategies to identify new therapeutic targets that when knocked down or inhibited can prevent metastasis and/or kill metastatic breast cancer cells. In the first approach, we are targeting genes specifically up-regulated in CREB3L1-deficient breast cancers. In the second approach, we are using a genome-wide shRNA screen to identify new gene targets that result in the selective killing of the highly metastatic CREB3L1-deficient breast cancer cells. Our goal is to identify new therapies for the ~30% of breast cancers that are CREB3L1-deficient and the most metastatic.

Title: New targets for highly metastatic CREB3L1-deficient breast cancer

November 29, 2017 - Dr. Sylvia van der Hurk, Univ. of Saskatchewan
Our overall goal is to perform a functional characterization of the impact of major tegument proteins of bovine herpesvirus-1 (BoHV-1) on viral fitness and the host response to infection. BoHV-1 has a severe impact on growth, milk production, and international livestock trade, thus causing major economic losses to the cattle industry. Herpesviruses are ubiquitous and composed of four concentric compartments, the nucleoprotein core, capsid, tegument and envelope. Compositionally, the tegument is the most complex, consisting of a proteinaceous complex of ~20 viral gene products that fills the space between the nucleocapsid and envelope. In BoHV-1 the tegument protein VP8 is by far the most abundant component of mature virions. VP8 is post-translationally modified by phosphorylation and O-linked glycosylation. While non-essential in vitro, deletion of VP8 leads to impaired virus replication in cultured cells. VP8 is indispensable in vivo, being essential for BoHV-1 to be able to infect cattle. Together with its abundance in the virion, this suggested that VP8 counteracts the host response early during infection. I will present results showing that VP8 is a major virulence factor in BoHV-1, performing multiple functions during the viral life cycle, some of which are correlated to its subcellular localization and/or regulated by phosphorylation.

Title: Phosphorylation and functions of VP8, a multitasker in bovine herpesvirus-1

December 6, 2017 - Dr. Eric Yen, Univ. of Wisconsin-Madison

The intestine plays a pivotal role in regulating systemic metabolism. It is the portal and sensor for incoming nutrients and the origin of neural and endocrine signals that determine responses to diet. Importantly, the intestine is the location where host, diet, and gut microbiota interact. We have discovered that acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) catalyzes triacylglycerol synthesis in enterocytes, mediates fat absorption in the intestine, and regulates whole body energy balance. Mice without a functional gene encoding the enzyme (Mogat2–/–) absorb a normal amount of dietary fat. However, they exhibit delayed fat absorption, altered gut hormone secretion, and increased energy expenditure. As a result, they are resistant to obesity and related metabolic disorders induced by a high-fat diet. Using tissue-specific gain- and loss-of-function models, we showed that intestinal MGAT2 enhances metabolic efficiency and promotes weight gain. When fed a fat-free diet, Mogat2–/– mice still exhibit increased energy expenditure, suggesting the effects are not limited to calories from fat. Accordingly, MGAT2 deficiency protects the genetically hyperphagic Agouti mouse fed a regular chow from excessive weight gain, hepatic steatosis, and glucose intolerance. We also found that inactivation of MGAT2 in adult mice decreases weight gain and enhances glucose regulation, even in already obese mice. Surprisingly, Mogat2–/– mice are also protected from both chemical and genetic insults to the pancreatic beta-cells. Based on our preliminary findings, we hypothesize that loss of MGAT2 might act on beta-cells through its effect on bile acid-modifying gut microbiota. Some of these findings and approaches we are taking to test this hypothesis will be discussed in this presentation.

Title: Triacylglycerol synthesis, energy metabolism, and glucose homeostasis: A gut reaction

January 10, 2018 - Dr. John Aitchison, Inst. System Biology, Seattle

Dr. John Aitchison is President and Director at the Center for Infectious Disease Research.   He also holds an appointment as Professor at the Institute for Systems Biology. As a student, he studied biochemistry, specializing in biotechnology and genetic engineering at McMaster University in Ontario, Canada. There, in the laboratory of Dr. Richard Rachubinski, he investigated the molecular mechanisms responsible for sorting proteins into peroxisomes. After receiving his PhD, Dr. Aitchison performed his postdoctoral work in the laboratory of Nobel Laureate Dr. Günter Blobel at Rockefeller University. In Dr. Blobel’s lab, Dr. Aitchison applied classic cell biology techniques and yeast genetics to the study of protein import into the nucleus. During this time, he began to apply large-scale proteomics to the problem, which he continued as an Assistant Professor in the Faculty of Medicine and Dentistry at the University of Alberta until joining the ISB as a founding faculty member in 2000.

Dr. Aitchison’s laboratory exploits systems-based assays and analyses to reveal and understand complex biological phenomena. For much of his career, his lab has focused on yeast as a model for developing systems biology approaches. He joined the Center for Infectious Disease Research in 2011 with the goal of bringing systems biology to infectious disease research and using the challenges of infectious diseases to further develop systems biology.  Dr. Aitchison maintains a joint position at ISB and CID Research, building a partnership between the two organizations and remaining at the cutting-edge of systems biology while bringing new developments to infectious disease research.

Dr. Aitchison also holds affiliate appointments at the University of Washington, University of Alberta, and University of British Columbia and Rockefeller University. He is a member of the Molecular and Cellular Biology and BPSD at the University of Washington.

Title: Systems cell biology: From organelle biogenesis in yeast to global health

January 17, 2018 - Dr. Brenda Bass, University of Utah

ABSTRACT: Viruses produce double-stranded RNA (dsRNA) during infection, and long dsRNA is also encoded and expressed in animal cells. dsRNA-binding proteins (dsRBPs) are not sequence specific, and we are interested in how cells discriminate cellular from viral dsRNA.

Ongoing studies are focused on the mechanisms by which two dsRBPs, ADAR and Dicer, mediate "self" versus "non-self" discrimination. Our studies indicate that in C. elegans, the ADAR RNA editing enzyme marks cellular long dsRNA as “self”. Studies of D. melanogaster Dicer-2 indicate its helicase domain is specialized for cleavage of viral, or "non-self", dsRNA.

Title: Is that my double-stranded RNA or yours?