A5070050490- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Cellular transport and secretion
- Multiple Myeloma Research and Treatments
- Diabetes Treatment and Management
- Peptidase Inhibition and Analysis
- HIV Research and Treatment
- Lipid Membrane Structure and Behavior
- Diet and metabolism studies
- Ubiquitin and proteasome pathways
- Mitochondrial Function and Pathology
- SARS-CoV-2 and COVID-19 Research
- Lysosomal Storage Disorders Research
- Complement system in diseases
- Parathyroid Disorders and Treatments
- Eicosanoids and Hypertension Pharmacology
- Venomous Animal Envenomation and Studies
- ATP Synthase and ATPases Research
- Protein Kinase Regulation and GTPase Signaling
- Renal and Vascular Pathologies
- Chromatin Remodeling and Cancer
- Platelet Disorders and Treatments
- Endoplasmic Reticulum Stress and Disease
- Renal Transplantation Outcomes and Treatments
- Muscle and Compartmental Disorders
Resverlogix (Canada)
2015-2024
University of California, Irvine
2022
VA Palo Alto Health Care System
2021
Amsterdam UMC Location University of Amsterdam
2020
University of Calgary
2019
McGill University
2001-2011
Montreal Neurological Institute and Hospital
2001-2011
University of Ottawa
2006-2007
Université de Montréal
1999
Montreal Clinical Research Institute
1999
Dynamin-related protein 1 (DRP1) plays an important role in mitochondrial fission at steady state and during apoptosis. Using fluorescence recovery after photobleaching, we demonstrate that healthy cells, yellow fluorescent (YFP)-DRP1 recycles between the cytoplasm mitochondria with a half-time of 50 s. Strikingly, apoptotic cell death, YFP-DRP1 undergoes transition from rapid recycling to stable membrane association. The cycling phase characterizes early stages apoptosis is independent...
Tandem MS has identified 209 proteins of clathrin-coated vesicles (CCVs) isolated from rat brain. An overwhelming abundance peptides were assigned to the clathrin coat with a 1:1 stoichiometry observed for heavy and light chains 2:1 chain adaptor protein heterotetramers. Thirty-two representing many known components synaptic (SVs) identified, supporting that main function brain CCVs is recapture SVs after exocytosis. A ratio vesicle- N -ethylmaleimide-sensitive factor attachment receptors...
In brain, mRNAs are transported from the cell body to processes, allowing for local protein translation at sites distant nucleus. Using subcellular fractionation, we isolated a fraction rat embryonic day 18 brains enriched structures that resemble amorphous collections of ribosomes. This was mRNA encoding beta-actin, an is in dendrites and axons developing neurons. Abundant components this fraction, determined by tandem mass spectrometry, include ribosomal proteins, RNA-binding...
Despite numerous advances in the identification of molecular machinery for clathrin-mediated budding at plasma membrane, mechanistic details this process remain incomplete. Moreover, relatively little is known regarding regulation other membrane systems. To address these issues, we have utilized powerful new approach subcellular proteomics to identify novel proteins present on highly enriched clathrin-coated vesicles (CCVs). Among ten identified rat homologue a predicted gene product from...
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach treating atherosclerosis through the stimulation reverse cholesterol transport. RVX-208 increases production ApoA-I in hepatocytes vitro, vivo monkeys humans, which results increased HDL-C, but molecular target was not previously reported. Using binding assays X-ray crystallography, we now show that selectively binds bromodomains BET (Bromodomain Extra Terminal) family, competing for site bound...
High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce risk cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription production in human primate primary hepatocytes. Accordingly, also significantly levels ApoA-I, HDL-associated cholesterol, HDL particle number...
Apabetalone (RVX-208) is a bromodomain and extraterminal protein inhibitor (BETi) that in phase II trials reduced the relative risk (RR) of major adverse cardiac events (MACE) patients with cardiovascular disease (CVD) by 44% diabetic CVD 57% on top statins. A III trial, BETonMACE, currently assessing apabetalone's ability to reduce MACE statin-treated post-acute coronary syndrome type 2 low high-density lipoprotein C. The leading cause atherosclerosis, driven dysfunctional lipid metabolism...
We recently identified polynucleotide phosphorylase (PNPase) as a potential binding partner for the TCL1 oncoprotein. Mammalian PNPase exhibits exoribonuclease and poly(A) polymerase activities, overexpression inhibits cell growth, induces apoptosis, stimulates proinflammatory cytokine production. A physiologic connection these anticancer effects is difficult to reconcile with presumed mitochondrial matrix localization endogenous PNPase, prompting this study. Here we show that basal...
Apabetalone is an inhibitor of bromodomain and extraterminal (BET) proteins. In clinical trials, apabetalone reduced the incidence major adverse cardiac events (MACE) in patients with cardiovascular disease circulating factors that promote vascular calcification (VC). Because VC contributes to MACE, effects on pro-calcific processes were examined.Apabetalone inhibited extracellular calcium deposition opposed induction transdifferentiation markers human coronary artery smooth muscle cells...
The Rho GTPases RhoA, Rac1, and Cdc42 play a major role in regulating the reorganization of actin cytoskeleton. We recently identified CdGAP, novel GTPase-activating protein with activity toward Rac1 Cdc42. CdGAP consists N-terminal GAP domain, central C-terminal proline-rich domain. Here we show that through subset its Src homology 3 domains, endocytic intersectin interacts CdGAP. In platelet-derived growth factor-stimulated Swiss 3T3 cells, co-localizes inhibits Rac1. Intersectin-Src also...
Apabetalone (RVX-208) is an epigenetic regulator developed to treat cardiovascular disease (CVD) that targets BET proteins. Through transcriptional regulation RVX-208 modulates pathways underlie CVD including reverse cholesterol transport, vascular inflammation, coagulation, and complement. Using transcriptomics proteomics we show complement one of the top downregulated by in primary human hepatocytes (PHH) plasma from patients. reduces basal cytokine-driven expression factors PHH chimeric...
Abstract Background Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing major adverse cardiac event. Dysregulation of epigenetic mechanisms gene transcription in innate immune cells contributes to CVD development but is currently not targeted by therapies. Apabetalone (RVX-208) small molecule inhibitor bromodomain extra-terminal (BET) proteins—histone acetylation readers that drive pro-inflammatory pro-atherosclerotic transcription....
Apabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has
Mammalian Son-of-sevenless (mSos) functions as a guanine nucleotide exchange factor for Ras and Rac, thus regulating signaling to mitogen-activated protein kinases actin dynamics. In the current study, we have identified new mSos-binding of 50 kDa (p50) that interacts with mSos1 proline-rich domain. Mass spectrometry analysis immunodepletion studies reveal p50 PACSIN 1/syndapin I, Src homology 3 domain-containing functioning in endocytosis regulation addition 1, which is neuron-specific,...
Epigenetic mechanisms are implicated in transcriptional programs driving chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain and extraterminal (BET) proteins, which epigenetic readers that modulate gene expression. In the phase 3 BETonMACE trial, apabetalone reduced risk major adverse cardiac events (MACE) by 50% CKD subpopulation, indicating favorable effects along kidney-heart axis. Activation human renal mesangial cells (HRMCs) to a contractile...
Aftiphilin was identified through a database search for proteins containing binding motifs the γ‐ear domain of clathrin adaptor protein 1 (AP‐1). Here, we demonstrate that aftiphilin is expressed predominantly in brain where it enriched on clathrin‐coated vesicles. In addition to eight γ‐ear‐binding motifs, contains two WXXF‐acidic mediate α‐ear 2 (AP‐2) and three FXXFXXF/L α‐ β2‐ear. We uses these interactions with AP‐1 AP‐2 immunoprecipitates APs but not AP‐3 or AP‐4 from extracts....
Apabetalone (RVX-208) inhibits the interaction between epigenetic regulators known as bromodomain and extraterminal (BET) proteins acetyl-lysine marks on histone tails. Data presented here supports manuscript published in Atherosclerosis "RVX-208, a BET-inhibitor for Treating Atherosclerotic Cardiovascular Disease, Raises ApoA-I/HDL Represses Pathways that Contribute to Disease" (Gilham et al., 2016) [1]. It shows RVX-208 comparator BET inhibitor (BETi) JQ1 increase mRNA expression...
Abstract Fabry disease (FD) is a rare X‐linked disorder of lipid metabolism, characterized by the accumulation globotriaosylceramide (Gb3) due to defective lysosomal enzyme, α‐galactosidase. Gb3 deposits activate immune‐mediated systemic inflammation, ultimately leading life‐threatening consequences in multiple organs such as heart and kidneys. Enzyme replacement therapy (ERT), standard care, less effective with advanced tissue injury inflammation patients FD. Here, we showed that MCP‐1...