A5077617262- Protease and Inhibitor Mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Signaling Pathways in Disease
- Phytochemistry and Bioactive Compounds
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Antiplatelet Therapy and Cardiovascular Diseases
- Platelet Disorders and Treatments
- Receptor Mechanisms and Signaling
- Connective Tissue Growth Factor Research
- Barrier Structure and Function Studies
- Angiogenesis and VEGF in Cancer
- Neuropeptides and Animal Physiology
- Biomarkers in Disease Mechanisms
- Chemokine receptors and signaling
- Cancer Mechanisms and Therapy
- Acute Myocardial Infarction Research
- Pancreatic and Hepatic Oncology Research
- Epigenetics and DNA Methylation
- Liver Disease Diagnosis and Treatment
- Biochemical and Structural Characterization
- Cancer, Lipids, and Metabolism
- Multiple Myeloma Research and Treatments
- Cholesterol and Lipid Metabolism
Molecular Oncology (United States)
2008-2023
Tufts University
2013-2023
Tufts Medical Center
2012-2023
Sinai Hospital
2015
Lahey Hospital and Medical Center
2013
Mount Auburn Hospital
2011-2013
Oregon Health & Science University
2012
Arthur M. Sackler Gallery
2012
Immunovaccine (Canada)
2009
Molecular Research Institute
2008
Classical ligands bind to the extracellular surface of their cognate receptors and activate signaling pathways without crossing plasma membrane barrier. We selectively targeted intracellular receptor–G protein interface by using cell-penetrating membrane-tethered peptides. Attachment a palmitate group peptides derived from third loop protease-activated receptors-1 -2 melanocortin-4 yields agonists and/or antagonists signaling. These lipidated peptides—which we have termed pepducins—require...
Thrombin activates platelets in an ordered sequence of events that includes shape change, increase cytoplasmic Ca2+, activation the αIIbβ3 integrin, granule secretion, aggregation, and formation a stable hemostatic plug. Activation this process has also been implicated pathogenesis atherosclerosis, stroke, thrombosis. There are two identified thrombin-activated receptors on surface human platelets. PAR1 is high-affinity thrombin receptor, PAR4 low apparent affinity receptor uncertain...
It has been hypothesized that protease-activated receptors may be activated and attenuated by more than one protease. Here, we explore a desensitization mechanism of the PAR1 thrombin receptor anticoagulant proteases provide an explanation to enigma why plasmin/tissue plasminogen activator (t-PA) can both activate deactivate platelets prior treatment. By using soluble N-terminal exodomain (TR78) as model for full-length receptor, were able unambiguously compare cleavage rates specificities...
Thrombin is the most potent agonist of platelets and plays a critical role in development arterial thrombosis. Human express dual thrombin receptors, protease-activated receptor (PAR) 1 PAR4; however, there are no therapeutic strategies that effectively target both receptors.Platelet aggregation studies demonstrated PAR4 activity markedly enhanced by thrombin-PAR1 interactions. A combination bivalirudin (hirulog) plus novel pepducin antagonist, P4pal-i1, inhibited human to even high...
Abstract Protease-activated receptor 1 (PAR1) is a G protein–coupled that not expressed in normal breast epithelia but up-regulated invasive carcinomas. In the present study, we found matrix metalloprotease-1 (MMP-1) robustly activates PAR1-Akt survival pathway carcinoma cells. This process blocked by cell-penetrating lipopeptide “pepducin,” P1pal-7, which potent inhibitor of cell viability cells expressing PAR1. Both MMP-1 and P1pal-7 significantly promote apoptosis tumor xenografts inhibit...
Protease-activated receptor-2 (PAR2), a cell surface receptor for trypsin-like proteases, plays key role in number of acute and chronic inflammatory diseases the joints, lungs, brain, gastrointestinal tract, vascular systems. Despite considerable effort by pharmaceutical industry, PAR2 has proven recalcitrant to targeting small molecule inhibitors, which have been unable effectively prevent interaction protease-generated tethered ligand with body receptor. Here, we report development...
Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report first human use a protease-activated receptor-1-based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications percutaneous coronary interventions.PZ-128 was administered by 1 2 hours continuous intravenous infusion (0.01-2 mg/kg) 31 subjects with artery disease or multiple risk factors. Safety, efficacy, and...
Abstract Sepsis is a deadly disease characterized by the inability to regulate inflammatory–coagulation response in which endothelium plays key role. The cause of this perturbation remains poorly understood and has hampered development effective therapeutics. Matrix metalloproteases (MMPs) are involved host pathogens, but can also uncontrolled tissue damage contribute mortality. We found that human sepsis patients had markedly elevated plasma proMMP‐1 active MMP‐1 levels, correlated with...
Abstract Ovarian cancer is a lethal gynecologic malignancy that may benefit from new therapies block key paracrine pathways involved in tumor-stromal interactions and tumor vascularity. It was recently shown matrix metalloprotease-1 (MMP1) activation of the G protein–coupled receptor protease-activated receptor-1 (PAR1) an important stimulator angiogenesis metastasis peritoneal mouse models ovarian cancer. In present study, we tested hypothesis MMP1-PAR1 promotes through its control...
Gene chip and proteomic analyses of tumors stromal tissue has led to the identification dozens candidate tumor host components potentially involved in tumor-stromal interactions, angiogenesis, progression invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers prognostic factors for metastatic cancers. From an initial screen benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, MMP-1 that...
Thrombin-dependent platelet activation is heightened in the setting of percutaneous coronary intervention and may cause arterial thrombosis with consequent myocardial necrosis. Given high incidence adverse effects patients acute syndromes, there remains an unmet need for development new therapeutics that target without unduly affecting hemostasis. The thrombin receptor, PAR1, has recently emerged as a promising therapeutic syndromes.We report first-in-class intracellular PAR1 inhibitor...
Insulin resistance and poor glycemic control are key drivers of the development NAFLD have recently been shown to be associated with fibrosis progression in NASH. However, underlying mechanisms involving dysfunctional glucose metabolism relationship NAFLD/NASH remain poorly understood. We set out determine whether protease-activated receptor 2 (PAR2), a sensor extracellular inflammatory coagulation proteases, links NASH liver metabolism.Here, we demonstrate that hepatic expression PAR2...
Bivalirudin, a direct thrombin inhibitor, is widely used adjunctive therapy in patients undergoing percutaneous intervention (PCI). Thrombin highly potent agonist of platelets and activates the protease-activated receptors, PAR1 PAR4, but it not known whether bivalirudin exerts antiplatelet effects PCI patients. We tested hypothesis that acts as an agent by preventing activation PARs on platelet surface.The effect function systemic levels was assessed elective PCI. Mean plasma were 2.7±0.5...
Emerging evidence suggests that protease-activated receptors-1 and -2 (PAR1 PAR2) can signal together in response to proteases found the rapidly changing microenvironment of damaged blood vessels. However, it is unknown whether PAR1 PAR2 promote or mitigate hyperplastic arterial injury. Using cell-penetrating pepducins mice deficient PAR2, we set out determine respective contributions receptors hyperplasia phenotypic modulation smooth muscle cells (SMCs) injury.SMCs were strongly activated...