A5056184568- Blood Coagulation and Thrombosis Mechanisms
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Protease and Inhibitor Mechanisms
- Receptor Mechanisms and Signaling
- Ion Channels and Receptors
- Neuropeptides and Animal Physiology
- Cell Adhesion Molecules Research
- Platelet Disorders and Treatments
- Food Allergy and Anaphylaxis Research
- Complement system in diseases
- Pain Mechanisms and Treatments
- Venomous Animal Envenomation and Studies
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- Pharmacological Receptor Mechanisms and Effects
- Adipose Tissue and Metabolism
- Biochemical Analysis and Sensing Techniques
- Biochemical and Structural Characterization
- Protein Kinase Regulation and GTPase Signaling
- Neurobiology and Insect Physiology Research
- Regulation of Appetite and Obesity
- Dermatology and Skin Diseases
- Osteoarthritis Treatment and Mechanisms
- Allergic Rhinitis and Sensitization
- Retinal Diseases and Treatments
Western University
2016-2025
University of Calgary
2011-2023
Université de Montréal
2017
Research Network (United States)
2013-2016
Toronto Western Hospital
2016
Libin Cardiovascular Institute of Alberta
2014
University of Illinois Chicago
2011
Canadian Institutes of Health Research
2009
Wythenshawe Hospital
2008
University of Manchester
2008
Human neutrophil proteinases (elastase, proteinase-3, and cathepsin-G) are released at sites of acute inflammation. We hypothesized that these inflammation-associated can affect cell signaling by targeting proteinase-activated receptor-2 (PAR2). The PAR family G protein-coupled receptors is triggered a unique mechanism involving the proteolytic unmasking an N-terminal self-activating tethered ligand (TL). Proteinases either activate TL sequence or disarm receptor for subsequent enzyme...
Transient Receptor Potential Melastatin–8 (TRPM8), a recently identified member of the transient receptor potential (TRP) family ion channels, is activated by mild cooling and chemical compounds such as supercooling agent, icilin. Since cooling, possibly involving TRPM8 stimulation, diminishes injury-induced peripheral inflammation, we hypothesized that activation may also attenuate systemic inflammation. We thus studied involvement in regulating colonic inflammation using two mouse models...
Neutrophil proteinases released at sites of inflammation can affect tissue function by either activating or disarming signal transduction mediated proteinase-activated receptors (PARs). Because PAR1 is expressed where abundant neutrophil infiltration occurs, we hypothesized that neutrophil-derived enzymes might also regulate signaling. We report here both elastase and proteinase-3 cleave the human N terminus distinct from thrombin cleavage site. This results in a thrombin-activated calcium...
We evaluated the ability of different trypsin-revealed tethered ligand (TL) sequences rat proteinase-activated receptor 2 (rPAR<sub>2</sub>) and corresponding soluble TL-derived agonist peptides to trigger agonist-biased signaling. To do so, we mutated proteolytically revealed TL sequence rPAR<sub>2</sub> examined impact on stimulating intracellular calcium transients mitogen-activated protein (MAP) kinase. The mutants, rPAR<sub>2</sub>-Leu<sup>37</sup>Ser<sup>38</sup>,...
Vibrio cholerae-derived zonula occludins toxin (Zot) is a multifunctional protein that reversibly disassembles intestinal tight junctions (tjs). Zot structure-function analysis has mapped this activity to aa 288–293, named AT1002. AT1002 reduced transepithelial electrical resistance across rat small intestine, ex vivo, as did and its processed mature form, ΔG. increased in vivo permeability sugar tracers, whereas scrambled control peptides not. Binding barrier assays proteinase activated...
Chronic kidney diseases cause significant morbidity and mortality in the population. During renal injury, kidney-localized proteinases can signal by cleaving activating proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor involved inflammation fibrosis that is highly expressed tubular cells. Following unilateral ureteric obstruction, PAR2-deficient mice displayed reduced fibrosis, collagen synthesis, connective tissue growth factor (CTGF), α-smooth muscle actin gene...
Thrombin is known to signal cells by cleaving/activating a G–protein–coupled family of proteinase-activated receptors (PARs). The signaling mechanism involves the proteolytic unmasking an N-terminal receptor sequence that acts as tethered receptor-activating ligand. To date, recognized targets thrombin cleavage and activation for are PAR1 PAR4, in which cleaves at conserved target arginine reveal PAR2, like also cleaved unmask its ligand, generally regarded trypsin but not signaling. We now...
MicroRNAs (miRNAs) are small noncoding RNA molecules, which known to regulate gene expression in physiological and pathological conditions. miRNA profiling was performed using brain tissue from patients with HIV encephalitis (HIVE), a neuroinflammatory/degenerative disorder caused by infection of the brain. Microarray analysis showed differential multiple miRNAs HIVE compared control brains. Target prediction ontology enrichment disclosed targeting several families/biological processes...
Myopia is a refractive disorder that degrades vision. It can be treated with atropine, muscarinic acetylcholine receptor (mAChR) antagonist, but the mechanism unknown. Atropine may block α-adrenoceptors at concentrations ≥0.1 mM, and another potent myopia-inhibiting ligand, mamba toxin-3 (MT3), binds equally well to human mAChR M4 α1A- α2A-adrenoceptors. We hypothesized antagonists could inhibit myopia via α2A-adrenoceptors, rather than M4.Human (M4), chicken (cM4), or α2A-adrenergic...
Transient receptor potential vanilloid-4 (TRPV4) is a calcium-permeant ion channel that known to affect vascular function. The ability of TRPV4 cause vasoconstriction in blood vessels has not yet been mechanistically examined. Further neuronal cells, signalling can be potentiated by GPCR activation. Thus, we studied the mechanisms underlying contractile action and GPCR-mediated potentiation such vasoconstriction, both which are as unappreciated aspects function.The TRPV4-dependent regulation...
Mucosal biopsies from inflamed colon of inflammatory bowel disease patients exhibit elevated epithelial apoptosis compared with those healthy individuals, disrupting mucosal homeostasis and perpetuating disease. Therapies that decrease intestinal may, therefore, ameliorate disease, but treatments specifically target apoptotic pathways are lacking. Proteinase-activated receptor-2 (PAR2), a G protein-coupled receptor activated by trypsin-like serine proteinases, is expressed on cells...
Lung fibroblasts are involved in interstitial lung disease, chronic asthma, and obstructive pulmonary disease (COPD). The expanded fibroblast population airway leads to remodeling contributes the inflammatory process seen these diseases. cation channel transient receptor potential vanilloid-1 (TRPV1) is activated by noxious stimuli, including capsaicin, protons, high temperatures thought have a role inflammation. Although TRPV1 expression primarily reported be neuronal, some extraneuronal...
SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive atherosclerosis, platelet accumulation in arteries, and myocardial fibrosis. Platelets are involved atherosclerosis development, PAR (protease-activated 4 has prominent role function mice. However, the of PAR4 on not been tested.We tested effects inhibitory pepducin (RAG8)...
In four experiments we examined the effect of an irrelevant drive on classical conditioning with food and water. first experiment weakened conditioned response in extinction. Experiments 2 3, this suppressive was found also acquisition. Furthermore, presence during nonreinforced presentations stimulus to protect from Experiment 4 showed that depressive is manifested only when relevant present. Taken together, these results suggest can influence responding by modulating representation...