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A mutation in the Na-K-2Cl cotransporter-1 leads to changes in cellular metabolism.
Omer S, Koumangoye R, Delpire E
(2020) J Cell Physiol 235: 7239-7250
MeSH Terms: Adolescent, Animals, Cell Line, DNA, Mitochondrial, Dogs, Energy Metabolism, Female, Fibroblasts, Glycolysis, Humans, Madin Darby Canine Kidney Cells, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microscopy, Electron, Transmission, Mitochondria, Multiple Organ Failure, Mutant Proteins, Mutation, Recombinant Fusion Proteins, Sequence Deletion, Solute Carrier Family 12, Member 2
Show Abstract · Added February 28, 2020
The Na-K-Cl cotransporter-1 (NKCC1), by mediating the electroneutral transport of Na , K , and Cl plays an important role in cell volume regulation, epithelial transport, and the control of neuronal excitability. Recently, we reported the first known human mutation in SLC12A2, the gene encoding NKCC1. The 17-year old patient suffers from multiorgan failure. Laboratory tests conducted on muscle and liver biopsies of the patient showed abnormal increase in mitochondrial DNA copy number and increased glycogen levels, indicating the possibility that the transporter may play a role in energy metabolism. Here, we show that fibroblasts isolated from the patient demonstrate a significant increase in mitochondrial respiration, compared to fibroblasts isolated from healthy individuals. Similarly, Madin Darby canine kidney (MDCK) cells transfected with enhanced green fluorescent protein (EGFP)-tagged mutant NKCC1 DNA demonstrated increased mitochondrial respiration when compared to MDCK cells expressing EGFP-tagged wild-type (WT) cotransporter. Direct inhibition of the cotransporter through addition of bumetanide did not change the rate of basal respiration, but led to increased maximal mitochondrial respiration. Fibroblasts extracted from NKCC1 and NKCC1 mice also demonstrated a significant elevation in mitochondrial respiration, compared to fibroblasts isolated from their WT littermates. Expression of the mutant protein was associated with an increase in hydrogen peroxide and peroxidase activity and a decrease in messenger RNA transcript levels for protein involved in the unfolded protein response. These data reveal that cells expressing the mutant cotransporter demonstrate increased mitochondrial respiration and behave like they are experiencing a state of starvation.
© 2020 Wiley Periodicals, Inc.
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22 MeSH Terms
Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A.
Sucre JMS, Vickers KC, Benjamin JT, Plosa EJ, Jetter CS, Cutrone A, Ransom M, Anderson Z, Sheng Q, Fensterheim BA, Ambalavanan N, Millis B, Lee E, Zijlstra A, Königshoff M, Blackwell TS, Guttentag SH
(2020) Am J Respir Crit Care Med 201: 1249-1262
MeSH Terms: Alveolar Epithelial Cells, Animals, Bronchopulmonary Dysplasia, Coculture Techniques, Fibroblasts, Gene Expression Profiling, Gene Expression Regulation, Developmental, Humans, Hyperoxia, In Situ Hybridization, Lung, Mesenchymal Stem Cells, Mice, Microscopy, Confocal, NF-kappa B, Nitriles, Organ Culture Techniques, Real-Time Polymerase Chain Reaction, Sulfones, Wnt-5a Protein
Show Abstract · Added February 6, 2020
Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at <32 weeks of gestation. Although the mechanisms driving BPD remain uncertain, exposure to hyperoxia is thought to contribute to disease pathogenesis. To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/β-catenin signaling after hyperoxia injury. Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA hybridization, quantitative confocal microscopy, and lung morphometry. Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of . Inhibition of Wnt5A abrogated the BPD transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A inhibition improved alveolarization following hyperoxia exposure, and treatment with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured in normoxic conditions. Chemical inhibition of NF-κB with BAY11-7082 reduced expression in the PCLS hyperoxia model and mouse hyperoxia model, with improved alveolarization in the PCLS model. Increased mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening observed in BPD. Precise targeting of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.
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20 MeSH Terms
Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Unlu G, Qi X, Gamazon ER, Melville DB, Patel N, Rushing AR, Hashem M, Al-Faifi A, Chen R, Li B, Cox NJ, Alkuraya FS, Knapik EW
(2020) Nat Med 26: 98-109
MeSH Terms: Abnormalities, Multiple, Animals, Behavior, Animal, Biological Specimen Banks, Chondrocytes, Disease Models, Animal, Extracellular Matrix, Fibroblasts, Guanine Nucleotide Exchange Factors, Humans, Models, Biological, Musculoskeletal System, Osteogenesis, Phenomics, Phenotype, Procollagen, Protein Transport, Secretory Pathway, Syndrome, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 15, 2020
Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.
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21 MeSH Terms
Stoichiometric optimization of Gata4, Hand2, Mef2c, and Tbx5 expression for contractile cardiomyocyte reprogramming.
Zhang Z, Zhang W, Nam YJ
(2019) Sci Rep 9: 14970
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, Cellular Reprogramming, Fibroblasts, GATA4 Transcription Factor, MEF2 Transcription Factors, Mice, Mice, Transgenic, Myocardial Contraction, Myocytes, Cardiac, Phenotype, Plasmids, T-Box Domain Proteins, Transcriptome, Transduction, Genetic
Show Abstract · Added March 24, 2020
Reprogramming of fibroblasts to induced cardiomyocyte-like cells (iCMs) offers potential strategies for new cardiomyocyte generation. However, a major challenge of this approach remains its low efficiency for contractile iCMs. Here, we showed that controlled stoichiometric expression of Gata4 (G), Hand2 (H), Mef2c (M), and Tbx5 (T) significantly enhanced contractile cardiomyocyte reprogramming over previously defined stoichiometric expression of GMT or uncontrolled expression of GHMT. We generated quad-cistronic vectors expressing distinct relative protein levels of GHMT within the context of a previously defined splicing order of M-G-T with high Mef2c level. Transduction of the quad-cistronic vector with a splicing order of M-G-T-H (referred to as M-G-T-H) inducing relatively low Hand2 and high Mef2c protein levels not only increased sarcomeric protein induction, but also markedly promoted the development of contractile structures and functions in fibroblasts. The expressed Gata4 and Tbx5 protein levels by M-G-T-H transduction were relatively higher than those by transductions of other quad-cistronic vectors, but lower than those by previously defined M-G-T tri-cistronic vector transduction. Taken together, our results demonstrate the stoichiometric requirement of GHMT expression for structural and functional progresses of cardiomyocyte reprogramming and provide a new basic tool-set for future studies.
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16 MeSH Terms
Ahead of their time: hyperoxia injury induces senescence in developing lung fibroblasts.
Sucre JMS, Plosa EJ
(2019) Am J Physiol Lung Cell Mol Physiol 317: L523-L524
MeSH Terms: Fibroblasts, Humans, Hyperoxia, Lung
Added March 18, 2020
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4 MeSH Terms
Inactivation of in Abcg2 lineage-derived cells drives the appearance of polycystic lesions and fibrosis in the adult kidney.
Gewin LS, Summers ME, Harral JW, Gaskill CF, Khodo SN, Neelisetty S, Sullivan TM, Hopp K, Reese JJ, Klemm DJ, Kon V, Ess KC, Shi W, Majka SM
(2019) Am J Physiol Renal Physiol 317: F1201-F1210
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Cell Lineage, Female, Fibrosis, Kidney Tubules, Proximal, Male, Mice, Myofibroblasts, Polycystic Kidney Diseases, Selective Estrogen Receptor Modulators, Tamoxifen, Tuberous Sclerosis Complex 2 Protein
Show Abstract · Added March 18, 2020
Tuberous sclerosis complex 2 (TSC2), or tuberin, is a pivotal regulator of the mechanistic target of rapamycin signaling pathway that controls cell survival, proliferation, growth, and migration. Loss of function manifests in organ-specific consequences, the mechanisms of which remain incompletely understood. Recent single cell analysis of the kidney has identified ATP-binding cassette G2 (Abcg2) expression in renal proximal tubules of adult mice as well as a in a novel cell population. The impact in adult kidney of knockdown in the Abcg2-expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated , lacking exons 36-37 with an intact 3' region and polycystin 1, is driven by Here, we demonstrate that selective expression of in the Abcg2 lineage drives recombination in proximal tubule epithelial and rare perivascular mesenchymal cells, which results in progressive proximal tubule injury, impaired kidney function, formation of cystic lesions, and fibrosis in adult mice. These data illustrate the critical importance of function in the Abcg2-expressing proximal tubule epithelium and mesenchyme during the development of cystic lesions and remodeling of kidney parenchyma.
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13 MeSH Terms
Identification of a pro-angiogenic functional role for FSP1-positive fibroblast subtype in wound healing.
Saraswati S, Marrow SMW, Watch LA, Young PP
(2019) Nat Commun 10: 3027
MeSH Terms: Actins, Animals, Bone Marrow Transplantation, Calcium-Binding Proteins, Cell Differentiation, Disease Models, Animal, Fibroblasts, Fibrosis, Green Fluorescent Proteins, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardial Infarction, Myocardium, Neovascularization, Physiologic, S100 Calcium-Binding Protein A4, Transplantation Chimera, Wound Healing
Show Abstract · Added March 24, 2020
Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.
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MeSH Terms
Age Mosaicism across Multiple Scales in Adult Tissues.
Arrojo E Drigo R, Lev-Ram V, Tyagi S, Ramachandra R, Deerinck T, Bushong E, Phan S, Orphan V, Lechene C, Ellisman MH, Hetzer MW
(2019) Cell Metab 30: 343-351.e3
MeSH Terms: Aging, Animals, Cellular Senescence, Cilia, Endothelial Cells, Female, Fibroblasts, Insulin-Secreting Cells, Liver, Mice, Mice, Inbred Strains, Mosaicism, Neurons, Organ Specificity, Pancreas
Show Abstract · Added April 14, 2021
Most neurons are not replaced during an animal's lifetime. This nondividing state is characterized by extreme longevity and age-dependent decline of key regulatory proteins. To study the lifespans of cells and proteins in adult tissues, we combined isotope labeling of mice with a hybrid imaging method (MIMS-EM). Using N mapping, we show that liver and pancreas are composed of cells with vastly different ages, many as old as the animal. Strikingly, we also found that a subset of fibroblasts and endothelial cells, both known for their replicative potential, are characterized by the absence of cell division during adulthood. In addition, we show that the primary cilia of beta cells and neurons contains different structural regions with vastly different lifespans. Based on these results, we propose that age mosaicism across multiple scales is a fundamental principle of adult tissue, cell, and protein complex organization.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.
Yao L, Wright MF, Farmer BC, Peterson LS, Khan AM, Zhong J, Gewin L, Hao CM, Yang HC, Fogo AB
(2019) Nephrol Dial Transplant 34: 2042-2050
MeSH Terms: Actins, Animals, Collagen Type I, Connective Tissue Growth Factor, Extracellular Matrix Proteins, Fibroblasts, Fibrosis, Kidney Diseases, Mice, Mice, Knockout, Nerve Tissue Proteins, Serpin E2, Transforming Growth Factor beta, Ureteral Obstruction
Show Abstract · Added March 18, 2020
BACKGROUND - Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1).
METHODS - Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later.
RESULTS - GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice.
CONCLUSION - These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.
© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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14 MeSH Terms
Allosteric Regulation of Oligomerization by a B Trafficking G-Protein Is Corrupted in Methylmalonic Aciduria.
Ruetz M, Campanello GC, McDevitt L, Yokom AL, Yadav PK, Watkins D, Rosenblatt DS, Ohi MD, Southworth DR, Banerjee R
(2019) Cell Chem Biol 26: 960-969.e4
MeSH Terms: Allosteric Regulation, Amino Acid Metabolism, Inborn Errors, Fibroblasts, Guanosine Triphosphate, Humans, Methylmalonyl-CoA Mutase, Molecular Chaperones, Mutation, Protein Transport, Vitamin B 12
Show Abstract · Added March 3, 2020
Allosteric regulation of methylmalonyl-CoA mutase (MCM) by the G-protein chaperone CblA is transduced via three "switch" elements that gate the movement of the B cofactor to and from MCM. Mutations in CblA and MCM cause hereditary methylmalonic aciduria. Unlike the bacterial orthologs used previously to model disease-causing mutations, human MCM and CblA exhibit a complex pattern of regulation that involves interconverting oligomers, which are differentially sensitive to the presence of GTP versus GDP. Patient mutations in the switch III region of CblA perturb the nucleotide-sensitive distribution of the oligomeric complexes with MCM, leading to loss of regulated movement of B to and/or from MCM and explain the molecular mechanism of the resulting disease.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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10 MeSH Terms