A5101868116- Blood Coagulation and Thrombosis Mechanisms
- Lipoproteins and Cardiovascular Health
- Hemophilia Treatment and Research
- Cell Adhesion Molecules Research
- Lipid Membrane Structure and Behavior
- Peripheral Artery Disease Management
- Atherosclerosis and Cardiovascular Diseases
- Monoclonal and Polyclonal Antibodies Research
- Antiplatelet Therapy and Cardiovascular Diseases
- RNA Interference and Gene Delivery
- Cancer, Lipids, and Metabolism
- Hormonal Regulation and Hypertension
- Platelet Disorders and Treatments
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Cancer Immunotherapy and Biomarkers
- Advanced biosensing and bioanalysis techniques
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Cerebrovascular and Carotid Artery Diseases
- Apelin-related biomedical research
- Renal cell carcinoma treatment
- Nanoparticles: synthesis and applications
- Protease and Inhibitor Mechanisms
- Biosimilars and Bioanalytical Methods
- Systemic Lupus Erythematosus Research
- Birth, Development, and Health
University of Toronto
2020-2024
Toronto General Hospital
2020-2024
University Health Network
2017-2024
Amgen (United States)
2009-2020
Moderna Therapeutics (United States)
2018
University of Notre Dame
1996-2002
KU Leuven
1999
Vlaams Instituut voor Biotechnologie
1997
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to epitope on PCSK9 adjacent region required LDLR interaction. In vitro, mAb1 inhibits binding attenuates PCSK9-mediated reduction in protein levels, thereby increasing uptake. A combination of statin increases levels HepG2 cells...
Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure. In cardiomyocytes, the synthesized as precursor, proatrial (pro-ANP), which proteolytically converted to active ANP. Corin transmembrane serine protease has been shown process pro-ANP in vitro, but its physiological importance had not established. Here, we show corin-deficient (Cor-/-) mice develop normally during embryogenesis and survive postnatal life. Cor-/- have elevated levels of no detectable ANP...
LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting clearance. The therapeutic potential for PCSK9 inhibitors is highlighted the fact that loss-of-function carriers exhibit 15–30% lower circulating and a disproportionately risk (47–88%) of experiencing cardiovascular event. Here, we utilized pcsk9−/− mice an anti-PCSK9 antibody study role receptor (LDLR) ApoE in PCSK9-mediated regulation plasma...
Heart failure (HF) remains a grievous illness with poor prognosis even optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and has potential to be novel target treat HF. Intravenous administration improves cardiac function acutely in patients However, its short half-life restricts use infusion therapy. To identify longer acting APJ agonist, we conducted medicinal chemistry campaign, leading discovery potent small-molecule...
Mice doubly heterozygous for a modified tissue factor pathway inhibitor (TFPI) allele (tfpiδ) lacking its Kunitz-type domain-1 (TFPI+/δ) and deficiency of the VII gene (FVII+/–) were mated to generate 309 postnatal 205 embryonic day 17.5 (E17.5) offspring having all predicted genotypic combinations. Progeny singly homozygous tfpiδ modification but with wild-type fVII (FVII+/+/TFPIδ/δ), mice possessing tfpi (FVII–/–/TFPI+/+), displayed previously detailed phenotypes (i.e., high percentage...
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive therapeutic target for cardiovascular disease. Monoclonal antibodies (mAbs) that bind PCSK9 and prevent PCSK9:low-density lipoprotein receptor complex formation reduce serum low-density lipoprotein-cholesterol (LDL-C) in vivo. PCSK9-mediated lysosomal degradation of bound mAb, however, dramatically reduces mAb exposure limits duration effect. Administration high-affinity mAb1:PCSK9 (1:2) to mice resulted...
We have previously proposed that a cluster of surface-exposed hydrophobic amino acids, viz., F4, L5, and L8, present at the amino-terminus Ca2+-bound form γ-carboxyglutamic acid domain (GD) human protein C (PC), contributes substantial portion total functional binding energy PC its activated form, APC, to acidic phospholipid (PL) vesicles. A deeper understanding importance nature sequence position 5, particular relevance leucine location, was sought by examination properties series mutant...
To determine whether an additional loss of the coagulation factor VII (FVII) gene influenced coagulopathy observed in protein C gene-deficient (PC(-/-)) embryos and neonates, we crossed mice doubly heterozygous for (FVII(+/-)) (PC(+/-)) genes to produce offspring possessing 9 predicted genotypic combinations. FVII(-/-)/PC(-/-) embryos, although present at their expected Mendelian frequency, displayed a phenotype that had not been either FVII or PC singly deficient embryos. At E12.5 days...