A5044222068- Endoplasmic Reticulum Stress and Disease
- Protease and Inhibitor Mechanisms
- Peptidase Inhibition and Analysis
- Autophagy in Disease and Therapy
- Genetics, Aging, and Longevity in Model Organisms
- Complement system in diseases
- Ubiquitin and proteasome pathways
- Blood Coagulation and Thrombosis Mechanisms
- Signaling Pathways in Disease
- Cellular transport and secretion
- RNA Interference and Gene Delivery
- Genetics and Neurodevelopmental Disorders
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Animal Genetics and Reproduction
- Studies on Chitinases and Chitosanases
- Monoclonal and Polyclonal Antibodies Research
- Drug Transport and Resistance Mechanisms
- Insect Resistance and Genetics
- Pediatric Hepatobiliary Diseases and Treatments
- Digestive system and related health
- Virus-based gene therapy research
- Adenosine and Purinergic Signaling
- S100 Proteins and Annexins
- Gastroesophageal reflux and treatments
- Antimicrobial Peptides and Activities
Washington University in St. Louis
1997-2024
Pediatrics and Genetics
2024
Lawrence Berkeley National Laboratory
2023-2024
James S. McDonnell Foundation
2024
University of Pittsburgh
2005-2019
Children's Hospital of Pittsburgh
2002-2015
Magee-Womens Hospital
2008-2014
Weatherford College
2014
Neurological Surgery
2010
Henry Ford Health System
2010
The monokine, cachectin/tumor necrosis factor (TNF) differs from interleukin 1 (IL-1) in primary structure and recognition by a distinct cellular receptor. It does, however, encode effector functions that are similar to those of IL-1 characteristic the host response inflammation or tissue injury. Accordingly, we examined possibility recombinant-generated human TNF regulates hepatic acute-phase gene expression. In picomolar concentrations, mediated reversible, dose- time-dependent increases...
Degradation of proteins that are retained in the quality control apparatus endoplasmic reticulum (ER) has been attributed to a third proteolytic system, distinct from lysosomal and cytoplasmic ubiquitin-dependent proteosomal pathways. However, several recent studies have shown ER degradation mutant membrane protein, CFTRΔF508, is at least part mediated side by 26 S proteasome. In this study, we examined possibility secretory protein α1-antitrypsin (α1-AT) Z, associated with infantile liver...
Liver injury in PiZZ alpha 1-antitrypsin (alpha 1-AT) deficiency probably results from toxic effects of the abnormal 1-AT molecule accumulating within ER liver cells. However, only 12-15% individuals with this same genotype develops disease. Therefore, we predicted that other genetic traits determine net intracellular accumulation mutant would also susceptibility to To address prediction, transduced skin fibroblasts disease or without amphotropic recombinant retroviral particles designed for...
Although there is evidence for specific subcellular morphological alterations in response to accumulation of misfolded proteins the endoplasmic reticulum (ER), it not clear whether these changes are stereotypical or if they depend on protein retained. This issue may be particularly important mutant secretory α 1 -antitrypsin (α AT) Z because retention this ER can cause severe target organ injury, chronic hepatitis/hepatocellular carcinoma associated with AT deficiency. Here we examined that...
During the host response to inflammation/tissue injury there are many changes in intermediary metabolism including a dramatic change concentrations of acute phase plasma proteins. Although these proteins predominantly derived from liver and can be elicited cells incubated tissue culture with cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor-alpha, interferon-gamma, leukemia inhibitory factor, interleukin-11 (IL-11), oncostatin M, is now evidence that also...
In alpha(1)-antitrypsin (alpha1AT) deficiency, a polymerogenic mutant form of the secretory glycoprotein alpha1AT, alpha1ATZ, is retained in endoplasmic reticulum (ER) liver cells. It not yet known how this results injury subgroup deficient individuals and remainder escapes disease. One possible explanation that "susceptible" unable to mount appropriate protective cellular responses. Here we examined effect alpha1ATZ on several potential signaling pathways by using cell lines with inducible...
Expression of the alpha 1-proteinase inhibitor (alpha 1PI) gene was studied in human mononuclear cells. Using RNA blot and dot hybridization, 1PI mRNA detected peripheral blood monocytes, bronchoalveolar breast milk macrophages, but not B or T lymphocytes. incorporation a radiolabeled amino acid precursor, synthesis secretion were demonstrated monocytes In addition, secreted functionally active form as shown by complexing with serine proteases. Biosynthesis phagocytes greatest during first...
Formation of the covalently stabilized complex alpha 1-antitrypsin (alpha 1-AT) with neutrophil elastase, archetype serine proteinase inhibitor serpin-enzyme complexes, is associated structural rearrangement 1-AT molecule and hydrolysis a reactive-site peptide bond. An approximately 4-kDa carboxyl-terminal cleavage fragment generated. 1-AT-elastase complexes are biologically active, possessing chemotactic activity mediating increases in expression gene human monocytes macrophages. This...
α-1-Antitrypsin (α1-AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury caused by toxicity mutant α-1-antitrypsin Z (α1-ATZ) molecule retained within hepatocytes. In these studies, we used PiZ transgenic mouse model α1-AT to examine hepatocellular proliferation in response chronic resulting from this The results showed increased and caspase 9 activation male mice compared with female wild-type mice. Hepatic mRNA protein expression also were...
alpha 1-Antitrypsin (alpha 1-AT) is an acute phase plasma protein predominantly derived from the liver which inhibits neutrophil elastase. Previous studies have suggested that 1-AT also expressed in human enterocytes because mRNA could be detected jejunum by RNA blot analysis, and synthesis a intestinal adenocarcinoma cell line Caco2, spontaneously differentiates into villous-like tissue culture. To definitively determine gene vivo, we examined slices of ileum situ hybridization. The results...
Interleukin-1 (IL-1) is a product of mononuclear phagocytes that mediates changes characteristic the response to inflammation or tissue injury (the acute-phase response). One two structurally and functionally homologous major histocompatibility complex (MHC) class III genes encodes positive protein, complement factor B. The closely linked C2 gene not affected during response. Purified human IL-1, p H 7.0, recombinant-generated murine 5.0, increased expression B other proteins in hepatoma...
The cytokine IFN beta 2/IL-6 has recently been shown to regulate the expression of genes encoding hepatic acute phase plasma proteins. INF also be identical MGI-2, a protein that induces differentiation bone marrow precursor cells toward mature granulocytes and monocytes. Accordingly, we have examined effect on IL-1- tumor necrosis factor-unresponsive alpha 1-antitrypsin (alpha 1 AT) in human hepatoma-derived hepatocytes mononuclear phagocytes. Purified fibroblast recombinant each mediate...
y-Interferon (IFN-y) is a well characterized lymphokine known to regulate many mononuclear phagocyte functions, including expression of class I and I1 major histocompatibility complex genes.The second component complement (C2) factor B are I11 gene products synthesized in phagocytes.Recombinant IFN-y increased the synthesis C2 primary cultures human phagocytes murine fibroblasts transfected with cosmid DNA bearing genes.In both cell types increases protein were detected at concentrations...
α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which synthesized by the liver, to inhibit neutrophil elastase, a protease degrades connective tissue lung. In classical form disease, inefficient secretion mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes reduced inhibitor activity, resulting injury pulmonary Because increases hepatocyte cell stress, we investigated whether...
In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation misfolded mutant Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates transplantation, others with same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from individuals or without SLD could model these...
Biliary atresia (BA) is the most common cause of end-stage liver disease in children and primary indication for pediatric transplantation, yet underlying etiologies remain unknown. Approximately 10% infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities complex cardiac malformations-a distinctive subgroup commonly referred to as biliary malformation (BASM) syndrome. We hypothesized that genetic factors linking features with etiopathogenesis...
Abstract Operando X-ray micro-computed tomography (µCT) provides an opportunity to observe the evolution of Li structures inside pouch cells. Segmentation is essential step quantitatively analyzing µCT datasets but challenging achieve on operando Li-metal battery due low attenuation metal and sheer size datasets. Herein, we report a computational approach, batteryNET, train Iterative Residual U-Net-based network detect structures. The resulting semantic segmentation shows singular Li-related...
The dissociation of the enzyme-inhibitor complex may result