Crif1 : Protein expression, purification and crystallisation

Human Crif1 is a protein with multiple functions, playing important roles in embryonic development, cellular stress, cell cycle regulation and mitochondrial membrane integrity. CRIF1 is coined to play a regulatory role in the Bone Marrow microenvironment-induced leukemia cell cycle arrest possibly through interacting with CDK2 and acting as a cyclin-dependent kinase inhibitor.
In this project, we will express human Crif1 protein in baculovirus system, purify it with affinity chromatography and followed by crystallisation.

Development and Delivery of Inhibitors for Viral Pathogenic Deubiquitinases - Year Two

In human viral diseases, misbehaviour of the cellular machinery utilizing ubiquitin is frequently observed. Ubiquitin is a small protein that attaches to target proteins in human cells and signals for their destruction. Human deubiquitinases are enzymes that remove ubiquitin to keep protein levels in balance. Viral pathogens have evolved proteins that mimic human deubiquitinases to evade the immune system by interfering with host ubiquitin-dependent processes.

Biomarkers of Spinal Cord Injury

In this project, we will establish biomarkers that objectively reflect the severity of injury, measure its progression, and predict neurologic outcome after acute spinal cord injury (SCI). This will be accomplished by comprehensively analyzing blood and spinal fluid samples from acute SCI patients. In addition, we will conduct a parallel experimental study in a large animal model of SCI with a similar analysis of blood and spinal fluid samples.

Development of a novel robust clone for the manufacturing of AVID100 biosimilar

AVID100 is an antibody-drug conjugate (ADC) against a validated cancer target that is undergoing IND-enabling studies. Phase I clinical trials are scheduled for late 2016. The monoclonal antibody (mAb) portion of the ADC is currently manufactured using a recombinant CHO clone that fails to meet industrial production yield standards. In order to support clinical phases II and III as well as commercial supply a higher-expressing cell line must be developed. MAb product characteristics will need to be similar to the current clone, namely with regards to the N-glycan composition.

Design and advancement of Graft Enabled Antibody Therapies (GrEAT)

Membrane proteins such as ion channels, transporters or G-protein coupled receptors (GPCRs) are excellent but difficult drug targets involved in a large number of life-threatening diseases and conditions. These proteins, over-expressed and essential for disease onset and progression, are naturally targeted by toxins from venomous organisms. During evolution, these toxins have been optimized to efficiently target physiologically-relevant proteins involved in ion channel opening or closure, thus incapacitating the prey or defending against predators.

Development of specific inhibitors and activators toassess the role of human Ephrin Receptors in health and disease

Signaling through the Eph family of cell surface receptors is crucial for embryonic development and the maintenance of adult tissues. Given the central role of the 14 Eph receptors in controlling cell fate, it is not surprising that they also play a central role in oncogenesis and other pathological conditions. However, the signaling mechanisms of Eph receptors are extremely complex, and developing an effective therapeutic intervention for a particular disease requires a comprehensive understanding of Eph function.

Engineering Synthetic D-Proteins as Novel and Transformative Molecular Therapeutics Against Cancer Targets

Proteins can exist in two forms: left-handed (L) or right-handed (D); however, for indeterminate reasons life on this planet only uses the L-form. When studied in more detail, both protein forms possess identical physiochemical and biological properties. Yet, D-proteins show minimal proteolytic degradation and fail to elicit immune responses in animals, due to their unnatural arrangement for recognition in biological systems. Accordingly, the proposed project seeks to develop synthetic D-proteins as biopharmaceutical molecules.

Optimization of novel drugs to treat cardiac arrhythmias

This project aims to validate and optimize drugs to treat heart rhythm disorders. The heart is a complex organ that uses tiny electrical signals to maintain a healthy rhythm. When these electrical signals are disturbed, it can change the regular rhythm, which can result in life-threatening consequences such as sudden cardiac death. Here, I will visualize one of the components of the heart that is responsible for the electrical signals, a specialized protein known as the ‘sodium channel’. I will look at the three-dimensional structure of this component both with and without drugs bound to it.

Modern tools for selecting disease-resistance traits in honey bees

Over the past six and a half years we have developed a way to measure disease resistance in honey bees using a molecular diagnostic approach, similar to the tests done every day in hospital laboratories. We have then used this method to selectively breed bees that are, indeed, more resistant to disease. This is akin to the selective breeding humans have practiced for millennia on all our agricultural crops and livestock, only using modern tools. It is not genetically modifying bees.

Identification of copy number variation biomarkers in patients with inflammatory bowel disease

Copy number variations (CNVs) are an important type of structural variation affecting pathogenesis of complex diseases, such as inflammatory bowel disease (IBD). Accurate detection of genomic regions with CNVs is crucial for understanding the etiology of IBD, as these regions contain likely drivers of disease development. Microarray technology provides single-nucleotide resolution genomic data and is considered one of the best measurement technologies to detect CNVs. This project will identify and characterize CNV in 340 IBD patients in Manitoba.

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