A5015968427- Liver Diseases and Immunity
- Pediatric Hepatobiliary Diseases and Treatments
- Cholangiocarcinoma and Gallbladder Cancer Studies
- MicroRNA in disease regulation
- Liver Disease Diagnosis and Treatment
- Amoebic Infections and Treatments
- Parasitic Infections and Diagnostics
- Telomeres, Telomerase, and Senescence
- Congenital Anomalies and Fetal Surgery
- Liver physiology and pathology
- NF-κB Signaling Pathways
- Cancer-related molecular mechanisms research
- Genetic factors in colorectal cancer
- Epigenetics and DNA Methylation
- Hepatitis B Virus Studies
- Liver Disease and Transplantation
- Genetic and Kidney Cyst Diseases
- DNA Repair Mechanisms
- Apelin-related biomedical research
- Ferroptosis and cancer prognosis
- Esophageal Cancer Research and Treatment
- Diet and metabolism studies
- Phagocytosis and Immune Regulation
- RNA modifications and cancer
- Mechanisms of cancer metastasis
Mayo Clinic
2015-2025
WinnMed
2015-2025
Mayo Clinic in Arizona
2014-2021
Institute of Neurobiology
2020
Center for Digestive and Liver Diseases
2009
Primary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence a pathophysiologically important phenotype in PSC. We assessed markers cellular and senescence-associated secretory (SASP) livers patients with PSC, primary biliary cirrhosis, hepatitis C, normals by fluorescent situ hybridization (FISH) immunofluorescence microscopy (IFM). whether endogenous exogenous constituents affect SASP cultured...
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested hypothesis that germ‐free (GF) mutltidrug resistance 2 knockout (mdr2 −/− ) mice develop distinct phenotype, compared to conventionally housed (CV) mdr2 mice. Mdr2 (n = 12) were rederived as GF by embryo transfer, maintained isolators, and sacrificed at 60 days parallel with...
Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach determine if spontaneous nuclear DNA damage sufficient initiate mammals. Ercc1-/∆ mice with reduced expression ERCC1-XPF endonuclease have impaired capacity repair the genome. accumulated spontaneous, oxidative more rapidly than wild-type (WT) mice. As consequence, compared repair-competent animals. levels never...
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads the activation stromal fibroblasts (ASFs), which are drivers fibrosis. The activated phenotype ASFs is characterized an increased sensitivity apoptotic stimuli. Here, we examined mechanisms priming in and explored a combined targeting strategy deplete from fibrotic tissue ameliorate liver Using coculture system, determined that promoted...
MicroRNAs, central players of numerous cellular processes, regulate mRNA stability or translational efficiency. Although these molecular events are established, the mechanisms regulating microRNA function and expression remain largely unknown. The let-7i regulates Toll-like receptor 4 expression. Here, we identify a novel transcriptional mechanism induced by protozoan parasite <i>Cryptosporidium parvum</i> Gram(−) bacteria-derived lipopolysaccharide (LPS) mediating promoter silencing in...
Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 CCA, we found no differences its mRNA level, suggesting posttranscriptional regulation, possibly microRNAs (miRNAs). Here, describe at least two HDAC6‐targeting miRNAs, miR‐433 and miR‐22, down‐regulated CCA both vitro vivo ....
Cholangiocytes, the epithelial cells lining bile ducts in liver, are periodically exposed to potentially injurious microbes and/or microbial products. As a result, cholangiocytes actively participate microbe-associated, hepatic proinflammatory responses. We previously showed that infection of cultured human with protozoan parasite, Cryptosporidium parvum, or treatment gram-negative bacteria-derived LPS, activates NFκB myeloid differentiation 88 (MyD88)-dependent manner. Here, we describe...
Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses the liver and contribute to inflammatory infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes proinflammatory/ proliferative responses. test hypothesis LPS-induced of requires EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal (NHC), were treated with LPS presence absence EGFR ADAM...
Abstract Purpose. Digital proteomic profiling was performed to identify spatial context in relationship patient response and survival after anti-PD-1 therapy metastatic colorectal cancer (CRC). Experimental Design. Primary CRCs with deficient mismatch repair (d-MMR) from patients treated antibodies were analyzed (N=30) using Spatial Profiling (GeoMx® nCounter). At the invasive margin, 71 proteins profiled 10 regions of interest /slide that segmented into 3 compartments labeled...
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by peribiliary inflammation and fibrosis. Cholangiocyte senescence prominent feature of PSC. Here, we hypothesize that extracellular vesicles (EVs) from senescent cholangiocytes influence the phenotype target cells.EVs were isolated normal human (NHCs), PSC patients NHCs experimentally induced to senescence. NHCs, malignant (MHCs) monocytes exposed 108 EVs each donor cell population assessed for proliferation, MAPK...
Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, express multiple toll-like receptors (TLRs) and, thus, have capacity to recognize and respond microbial pathogens. In previous work, we demonstrated that TLR4, which is activated by gram-negative lipopolysaccharide (LPS), upregulated in cholangiocytes response infection with Cryptosporidium parvum vitro contributes nuclear factor-kappaB (NF-kB) activation. Here, using an vivo model of biliary cryptosporidiosis, addressed...
The cholangiopathies are a diverse group of biliary tract disorders, many which lack effective treatment. Murine models an important tool for studying their pathogenesis, but existing noninvasive methods assessing disease in vivo not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop technique live-mouse cholangiography. Using mdr2 knockout (mdr2KO, model primary sclerosing cholangitis (PSC)), bile...
Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory cholangiopathy (disease of the bile ducts) unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and neuroblastoma RAS viral oncogene homolog (NRAS) activated cholangiocytes. Additionally, persistent microbial insult (
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive cholangiopathy. Cholangiocyte senescence important in PSC pathogenesis, and we have previously reported that regulated by the transcription factor ETS proto-oncogene 1 (ETS1) associated with overexpression of BCL2 like (BCL2L1 or BCL-xL), anti-apoptotic BCL2-family member. Here, further explored mechanisms regulating BCL-xL-mediated, apoptosis resistance senescent cholangiocytes uncovered ETS1 histone acetyltransferase...
Abstract Backgrounds and Aims Polycystic liver disease (PLD) is characterized by defective cholangiocyte cilia that regulate progressive growth of hepatic cysts. Because formation primary influenced autophagy through degradation proteins involved in ciliogenesis, we hypothesized ciliary defects PLD cholangiocytes (PLDCs) originate from autophagy‐mediated depletion ciliogenic ADP‐ribosylation factor‐like protein 3 (ARL3) 13B (ARL13B) ARL‐dependent mislocation a ciliary‐localized bile acid...
Internalization of the obligate intracellular apicomplexan parasite, Cryptosporidium parvum, results in formation a unique intramembranous yet extracytoplasmic niche on apical surfaces host epithelial cells, process that depends cell membrane extension. We previously demonstrated efficient C. parvum invasion biliary cells (cholangiocytes) requires actin polymerization and localized translocation/insertion Na(+)/glucose cotransporter 1 (SGLT1) aquaporin (Aqp1), water channel, at attachment...