A5037985824- Liver physiology and pathology
- Liver Disease Diagnosis and Treatment
- Phagocytosis and Immune Regulation
- Extracellular vesicles in disease
- Kruppel-like factors research
- Axon Guidance and Neuronal Signaling
- Fibroblast Growth Factor Research
- Angiogenesis and VEGF in Cancer
- Liver Disease and Transplantation
- Alcohol Consumption and Health Effects
- Pediatric Hepatobiliary Diseases and Treatments
- Syphilis Diagnosis and Treatment
- Endoplasmic Reticulum Stress and Disease
- Cellular Mechanics and Interactions
- Hippo pathway signaling and YAP/TAZ
- Genetic and Kidney Cyst Diseases
- Dialysis and Renal Disease Management
- Protease and Inhibitor Mechanisms
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Advanced Glycation End Products research
- Nuclear Receptors and Signaling
- Autophagy in Disease and Therapy
- Wnt/β-catenin signaling in development and cancer
- Apelin-related biomedical research
- Mechanisms of cancer metastasis
Mayo Clinic
2012-2024
WinnMed
2013-2024
Mayo Clinic in Arizona
2009-2024
Mayo Clinic in Florida
2023
Institute of Child Health
2015
Institute of Molecular Biology and Biophysics
2014
Yale University
2012
National Cancer Institute
2012
University of Illinois Chicago
2009
PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, mechanisms regulate PDGF signaling remain incompletely defined. Here, we found two rat models of fibrosis, axonal guidance molecule neuropilin-1 (NRP-1) was upregulated activated HSCs, which exhibit highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor β (PDGFRβ) HSCs both injury human HSC...
The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion proliferation. Here, we report that neuropilin-1 (NRP-1) orchestrates communications between soluble fibronectin promote α5β1 integrin-dependent fibril assembly, stiffness, growth. Tumor growth assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from in vivo. Mechanistically, the increase required glycosylation serine 612 extracellular domain...
Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs), followed matrix deposition. Recently, several studies have shown importance extracellular vesicles (EVs) derived from liver cells, such as hepatocytes endothelial in pathobiology. While most describe how modulate HSC behavior, an important gap exists understanding HSC‐derived signals more specifically EVs fibrosis. Here, we investigated molecules released through EVs, mechanism their release,...
During liver fibrosis, sinusoidal endothelial cells (LSECs) release angiocrine signals to recruit inflammatory into the liver. p300, a master regulator of gene transcription, is associated with pathological response. Therefore, we examined how p300 regulates signaling and inflammation related portal hypertension fibrogenesis.CCl4 or partial inferior vena cava ligation (pIVCL) was used induce injury. Mice LSEC-specific deletion (p300LSECΔ/Δ ) C-C motif chemokine ligand 2 (Ccl2) deficiency,...
Background & AimsTransdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived (PDGF) are canonical HSC activators after injury. The aim this study was to analyze epigenetic modulators that differentially control TGF-β PDGF signaling pathways.MethodsWe performed transcriptomic comparison HSCs treated with or PDGF-BB using RNA sequencing. Among targets distinguish these 2...
Sphingosine kinase 1 (SK1) is an FGF-inducible gene responsible for generation of sphingosine-1-phosphate, a critical lipid signaling molecule implicated in diverse endothelial cell functions. In this study, we identified SK1 as target the canonical FGF2/FGF receptor activation pathway cells and sought to identify novel transcriptional pathways that mediate signaling. Studies using 1.9-kb promoter deletion mutants revealed basal FGF2-stimulated activity occurred through two GC-rich regions...
Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), release fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation EV-related pericentral zone,...
Objectives/Goals: Primary sclerosing cholangitis (PSC) manifests with an inflammatory milieu that leads to fibrotic scarring of the liver. Human PSC liver bile ducts are enriched neutrophils; however, their infiltration and functional role is unexplored. Our goal investigate mechanism impact peribiliary neutrophil observed in PSC. Methods/Study Population: cholangiocytes (bile duct cells) isolated from WT mouse models (3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice Mdr2-/- mice)...
Hepatic stellate cells (HSC) and liver endothelial (LEC) migrate to sites of injury perpetuate alcohol-induced injury. High-mobility group box 1 (HMGB1) is a protein released from the nucleus injured that has been implicated as proinflammatory mediator. We hypothesized HMGB1 may be ethanol-stimulated parenchymal contribute HSC LEC recruitment. Ethanol stimulation rat hepatocytes HepG2 resulted in translocation assessed by Western blot. levels were increased supernatant ethanol-treated...
Objective— Farnesoid X Receptor (FXR) mediates important signaling functions of bile acids in diverse cell types including those residing the vascular wall. Indeed, recent work has identified FXR as a potential regulator structure and function part through transcriptional activation MMP-9. However, signal transduction pathways linking to changes actin cytoskeleton that are responsible for acid-induced migration remain unexplored. Methods Results— The agonist prototypical acid,...
Binding of angiogenic molecules with cognate receptor tyrosine kinases (RTK) is required for angiogenesis however the precise link between RTK binding, endocytosis, and signaling requires further investigation. Here, we use FGFR1 as a model to test effects large GTPase endocytosis regulatory molecule dynamin-2 on in context distinct FGF ligands. In vitro, overexpression dominant negative (DynK44A) attenuates activation Erk tubulogenesis by FGF2. Furthermore, identify FGF21, non-classical,...
Transforming growth factor (TGF-β)-induced activation of quiescent hepatic stellate cells (HSCs) and their transformation to myofibroblasts is a key event in liver fibrosis portal hypertension. GIPC (also referred as synectin) downstream signal molecule TGF-β other receptors. In this study, we sought identify novel genes targeted by elucidate if how they may contribute fibrosis.
Portal hypertension (PHTN) is a severe complication of liver cirrhosis and associated with intrahepatic sinusoidal remodeling induced by resistance angiogenesis. Collagen type IV (COL4), major component basement membrane, forms in sinusoids upon chronic injury. However, the role, cellular source, expression regulation COL4 diseases are unknown. Here, we examined how produced it regulates fibrosis PHTN. Human cirrhotic sample RNA sequencing showed increased expression, which was further...
The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor (PDGFR) is essential for hepatic stellate cell (HSC) activation liver fibrosis, we sought to determine on PDGFR pathway development fibrosis. Mice with deletion from HSC were found be protected mRNA sequencing revealed that knockdown demonstrated reductions fibrosis genes, including PDGFR-β. Chromatin IP assay PDGFR-β promoter upon pattern...
Nitric oxide (NO) regulates the function of perivascular cells (pericytes), including hepatic stellate (HSC), mainly by activating cGMP and cGMP-dependent kinase (PKG) via NO/cGMP paracrine signaling. Although PKG is implicated in integrin-mediated cell adhesion to extracellular matrix, whether or how signaling assembly focal complexes (FA) migration HSC not known. With help complementary molecular biological approaches, we demonstrate here that activation inhibits vascular tubulogenesis,...