A5044460018- Glycosylation and Glycoproteins Research
- Lysosomal Storage Disorders Research
- Cellular transport and secretion
- Sperm and Testicular Function
- Erythrocyte Function and Pathophysiology
- Atherosclerosis and Cardiovascular Diseases
- Endoplasmic Reticulum Stress and Disease
- Cholesterol and Lipid Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Galectins and Cancer Biology
- Lipoproteins and Cardiovascular Health
- Adipokines, Inflammation, and Metabolic Diseases
- Trypanosoma species research and implications
- Liver Disease Diagnosis and Treatment
- Carbohydrate Chemistry and Synthesis
- Clusterin in disease pathology
- Calcium signaling and nucleotide metabolism
- Autophagy in Disease and Therapy
- Nuclear Receptors and Signaling
- Cytomegalovirus and herpesvirus research
- Testicular diseases and treatments
- Bone and Dental Protein Studies
- Reproductive Biology and Fertility
- Parathyroid Disorders and Treatments
- Enzyme Production and Characterization
McMaster University
2012-2024
McMaster University Medical Centre
2020-2024
Queen's University
2024
Thrombosis and Atherosclerosis Research Institute
2014
Hamilton Health Sciences
2014
Montreal Children's Hospital
1997-2004
McGill University
1993-2004
Western University
1994
University of Victoria
1989
Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated effect of CF on expression two bona fide regulators circulating low-density lipoprotein cholesterol (LDLc) levels; proprotein convertase subtilisin/kexin type 9 (PCSK9) and receptor (LDLR). Following observation reduced PCSK9 levels increased hepatic LDLR expression, additional CF-derived analogs with potency for...
We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption the Hexa (α subunit) or Hexb (β genes, respectively, encoding lysosomal β-hexosaminidase A (structure, α) B ββ). Both mutant mice accumulate GM2 ganglioside in brain, much more so −/− mice, latter also glycolipid GA2. suffer no obvious behavioral neurological deficit, while develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor ataxia. The but not massive...
Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative resulting from the inability to catabolize GM2 ganglioside by β-hexos-aminidase A (Hex A) due mutations of α subunit (Tay-Sachs disease) or β (Sandhoff Hex A. B ( ββ homodimer) is also defective in disease. We previously developed mouse models both showed that Hexa-−/− (Tay-Sachs) mice remain asymptomatic at least 1 year age while Hexb−/− (Sandhoff) succumb a profound disease 4–6 months age. Here we find neuron death...
The present study was designed to determine the specific roles played by lysosomes and proteasomes in degradation of Cx43 both gap junctional intercellular communication-deficient MDA-MB-231 -competent BICR-M1Rk cells. In cells, immunolocalization brefeldin A protein transport blocking studies revealed that there a propensity for newly synthesized be transported lysosomes. On other hand, light electron microscopic analysis cells showed junctions were prevalent with subpopulation...
The fatty acid translocase, also known as CD36, is a well-established scavenger receptor for (FA) uptake and abundantly expressed in many metabolically active tissues. In the liver, CD36 to contribute progression of non-alcoholic liver disease more severe steatohepatitis, by promoting triglyceride accumulation subsequent lipid-induced endoplasmic reticulum (ER) stress. Given recent discovery that hepatocyte-secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) blocks expression, we...
Objective— Deficiency of the high-density lipoprotein receptor, scavenger receptor class B, type I (SR-BI), in apolipoprotein E knockout or hypomorphic mice, respectively, results spontaneous diet-inducible occlusive coronary artery (CA) atherosclerosis, myocardial infarction, and early death. Here, we examine effects SR-BI deficiency on cardiovascular phenotypes low-density (LDLR) mice fed different atherogenic diets. Approach Results— SR-BI/LDLR double control LDLR were diets containing...
PCSK9 modulates the uptake of circulating lipids through a range receptors, including low-density lipoprotein receptor (LDLR) and CD36. In kidney, CD36 is known to contribute renal injury pro-inflammatory -fibrotic pathways. this study, we sought investigate role in modulating lipid accumulation using high fat diet (HFD)-induced murine model.The effect on expression intracellular was examined cultured cells kidneys male C57BL/6J mice. The these findings subsequently explored model...
Sandhoff disease (SD) is a lysosomal storage disorder caused by lack of functional β-subunit the β-hexosaminidase A and B enzymes, leading to accumulation gangliosides in central nervous system (CNS). The Hexb−/− mouse model SD shows progressive neurodegenerative phenotype similar human equivalent. Previous studies have revealed that Hexb−/−mice suffer from chronic neuroinflammation characterized microglial activation expansion. Tumor necrosis factor-α (TNFα), key modulator CNS immune...
Lipoprotein metabolism is an important contributing factor in the development and progression of atherosclerosis. Plasma lipoproteins their receptors are heavily glycosylated sialylated, levels sialic acids modulate biological functions. Sialylation controlled by activities sialyltranferases sialidases. To address impact sialidase (neu1) activity on lipoprotein metabolism, we have generated a mouse model with hypomorphic neu1 allele (B6.SM) that displays reduced expression activity. The...
Monocyte recruitment leads to accumulation of macrophage foam cells and contributes atherosclerotic lesion growth. Recent studies have reported that lesion-resident macrophages can proliferate represent a major cellular component during development. This study was designed assess whether the rate proliferation changes well-established stages growth characterize other populations proliferating within these lesions.Using murine models atherosclerosis (Apoe(-/-) LDLr(-/-) mice) human coronary...
Apolipoprotein J/clusterin/sulfated glycoprotein-2 (apo J) disassociates from spermatozoa and is endocytosed by epithelial cells lining the efferent ducts epididymis. The low density lipoprotein receptor-related protein-2/megalin (LRP-2) has been shown to bind apo J mediates its endocytosis lysosomal degradation in cultured cells. In this study, immunocytological techniques were used localize LRP-2 rat epididymis determine whether expression correlated with those involved endocytosis....
Cathepsins are specific proteases in lysosomes that participate the degradation of proteins, some which derived from endocytosis. In this study we examined immunocytochemical localization cathepsin B and D antibodies cells rat testis epididymis, using light electron microscopic immunocytochemistry. testis, was immunolocalized over Sertoli Leydig on acrosome spermatids. Cathepsin found macrophages. Non-ciliated efferent ducts revealed intense immunogold labeling with both anti-cathepsin...
The proprotein convertase subtilisin/kexin type-9 (PCSK9) plays a central role in cardiovascular disease (CVD) by degrading hepatic low-density lipoprotein receptor (LDLR). As such, loss-of-function (LOF) PCSK9 variants that fail to exit the endoplasmic reticulum (ER) increase LDLR levels and lower risk of developing CVD. retention misfolded protein ER can cause stress activate unfolded response (UPR). In this study, we investigated whether variety LOF are retained cytotoxicity. Although...
Lysosomal sialidase occurs in a multienzyme complex that also contains β-galactosidase and cathepsin A. We previously cloned the human lysosomal cDNA characterized mutations sialidosis patients. Here, we report cloning expression of mouse gene. The 1.77 kb encodes an open reading frame 408 amino acids which shows high homology to (80%), rat cytosolic (65%) viral bacterial sialidases (50–55%). gene is ∼4 long six exons. five in-trons range size from 96 1200 bp. Northern blot analysis revealed...
SR-BI deficient mice that are also hypomorphic for apolipoprotein E expression develop diet induced occlusive coronary artery atherosclerosis, myocardial infarction and early death. To test the role of in bone marrow derived cells, we used transplantation to generate SR-BI-null; apoE-hypomorphic which was restored solely cells. were transplanted with SR-BI+/+apoE-hypomorphic, or control, autologous marrow. Four weeks later, fed a high-fat, high-cholesterol, cholate-containing induce...
Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis rare characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA four unrelated patients was screened for mutations within the sialidase gene NEU1. Five novel were identified. Four are missense one nonsense: c.674G>C (p.R225P), c.893C>T (p.A298V), c.3G>A (p.M1?), c.941C>G (p.R341G), c.69G>A (p.W23X). We have used our findings...
Scavenger receptor, class B, type I (SR-BI) mediates binding and internalization of a variety lipoprotein nonlipoprotein ligands, including HDL. Studies in genetically engineered mice revealed that SR-BI plays an important role HDL reverse cholesterol transport protection against atherosclerosis. Understanding how SR-BI's function is regulated may reveal new approaches to therapeutic intervention atherosclerosis heart disease. We utilized model cell system explore pathways involved...