PLoS Articles
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UNC-authored articles published by the Public Library of Science (PLoS)
Works (2112)
1641. Correction: Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1
- Title Tesim:
- Correction: Insulin and mTOR Pathway Regulate HDAC3-Mediated Deacetylation and Activation of PGK1
- Creator:
- Jiang, Bowen, Wang, Yi, Zhang, Tengfei, Chen, Xiufei, Guan, Kun-Liang, Xiong, Yue, Liu, Lixia, Ye, Dan, Lin, Huaipeng, Wang, Shiwen, Xia, Yukun, Wang, Yiping, Yang, Chen, Zhou, Lisha, and Chen, Leilei
- Date of publication:
- 2015
- Abstract Tesim:
- Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. Here, we report that PGK1 is acetylated at lysine 220 (K220), which inhibits PGK1 activity by disrupting the binding with its substrate, ADP. We have identified KAT9 and HDAC3 as the potential acetyltransferase and deacetylase, respectively, for PGK1. Insulin promotes K220 deacetylation to stimulate PGK1 activity. We show that the PI3K/AKT/mTOR pathway regulates HDAC3 S424 phosphorylation, which promotes HDAC3-PGK1 interaction and PGK1 K220 deacetylation. Our study uncovers a previously unknown mechanism for the insulin and mTOR pathway in regulation of glycolytic ATP production and cellular redox potential via HDAC3-mediated PGK1 deacetylation.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/n1ve-9q15
- Identifier:
- Onescience id: f6b50584a55747b2665b52a6cb5d7f93ff71a369, PMCID: PMC4565669, PMID: 26356530, and Publisher DOI: https://doi.org/10.1371/journal.pbio.1002243
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 9
- Journal Title:
- PLoS Biology
- Journal Volume:
- 13
- Keyword:
- HEK293 Cells, Mice, Inbred BALB C, Glycolysis, TOR Serine-Threonine Kinases, Enzyme Activation, Animals, Carbohydrate Metabolism, Histone Acetyltransferases, Histone Deacetylases, Male, Humans, Adenosine Diphosphate, Acetylation, Nerve Tissue Proteins, Oxidation-Reduction, Signal Transduction, and Phosphoglycerate Kinase
- Language Label:
- English
- Page Start:
- e1002243
- Person:
- Jiang, Bowen, Wang, Yi, Zhang, Tengfei, Chen, Xiufei, Guan, Kun-Liang, Xiong, Yue, Liu, Lixia, Ye, Dan, Lin, Huaipeng, Wang, Shiwen, Xia, Yukun, Wang, Yiping, Yang, Chen, Zhou, Lisha, and Chen, Leilei
- Rights Statement Label:
- In Copyright
- Source:
- ft849021s
1642. Ancient and Novel Small RNA Pathways Compensate for the Loss of piRNAs in Multiple Independent Nematode Lineages
- Title Tesim:
- Ancient and Novel Small RNA Pathways Compensate for the Loss of piRNAs in Multiple Independent Nematode Lineages
- Creator:
- Hanelt, Ben, Schiffer, Phillip M., Ardila-Garcia, Alex, Fast, Naomi M., Miska, Eric A., Sarkies, Peter, Selkirk, Murray E., Kraus, Christopher, Koutsovoulos, Georgios, Blaxter, Mark L., Taylor, Mark J., Jones, John T., Goldstein, Bob, Blok, Vivian, and Boothby, Thomas
- Date of publication:
- 2015
- Abstract Tesim:
- Small RNA pathways act at the front line of defence against transposable elements across the Eukaryota. In animals, Piwi interacting small RNAs (piRNAs) are a crucial arm of this defence. However, the evolutionary relationships among piRNAs and other small RNA pathways targeting transposable elements are poorly resolved. To address this question we sequenced small RNAs from multiple, diverse nematode species, producing the first phylum-wide analysis of how small RNA pathways evolve. Surprisingly, despite their prominence in Caenorhabditis elegans and closely related nematodes, piRNAs are absent in all other nematode lineages. We found that there are at least two evolutionarily distinct mechanisms that compensate for the absence of piRNAs, both involving RNA-dependent RNA polymerases (RdRPs). Whilst one pathway is unique to nematodes, the second involves Dicer-dependent RNA-directed DNA methylation, hitherto unknown in animals, and bears striking similarity to transposon-control mechanisms in fungi and plants. Our results highlight the rapid, context-dependent evolution of small RNA pathways and suggest piRNAs in animals may have replaced an ancient eukaryotic RNA-dependent RNA polymerase pathway to control transposable elements.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/wb64-kj97
- Identifier:
- PMCID: PMC4323106, Publisher DOI: https://doi.org/10.1371/journal.pbio.1002061, PMID: 25668728, and Onescience id: 495af90bb4168889baa13243cd72e4ba32fc6913
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 2
- Journal Title:
- PLoS Biology
- Journal Volume:
- 13
- Keyword:
- Humans, Molecular Sequence Data, Caenorhabditis elegans Proteins, Base Sequence, DNA Transposable Elements, Biological Evolution, Amino Acid Sequence, Nematoda, DNA Methylation, Animals, Caenorhabditis elegans, Drosophila melanogaster, MicroRNAs, and Gene Expression Regulation
- Language Label:
- English
- Page Start:
- e1002061
- Person:
- Hanelt, Ben, Schiffer, Phillip M., Ardila-Garcia, Alex, Fast, Naomi M., Miska, Eric A., Sarkies, Peter, Selkirk, Murray E., Kraus, Christopher, Koutsovoulos, Georgios, Blaxter, Mark L., Taylor, Mark J., Jones, John T., Goldstein, Bob, Blok, Vivian, and Boothby, Thomas
- Rights Statement Label:
- In Copyright
- Source:
- t435gn10p
1643. Not Just a Theory—The Utility of Mathematical Models in Evolutionary Biology
- Title Tesim:
- Not Just a Theory—The Utility of Mathematical Models in Evolutionary Biology
- Creator:
- Dhole, Sumit, Goldberg, Emma E., Van Cleve, Jeremy, Brandvain, Yaniv, Yeh, D. Justin, Fitzpatrick, Courtney L., Servedio, Maria R., and Stern, Caitlin A.
- Date of publication:
- 2014
- Abstract Tesim:
- Models have made numerous contributions to evolutionary biology, but misunderstandings persist regarding their purpose. By formally testing the logic of verbal hypotheses, proof-of-concept models clarify thinking, uncover hidden assumptions, and spur new directions of study. thumbnail image credit: modified from the Biodiversity Heritage Library
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/e5q7-kt44
- Identifier:
- PMID: 25489940, Publisher DOI: https://doi.org/10.1371/journal.pbio.1002017, Onescience id: 570f5c781ee7bb52e0718ce85a73c6f9480745f3, and PMCID: PMC4260780
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 12
- Journal Title:
- PLoS Biology
- Journal Volume:
- 12
- Keyword:
- Ontologies, Mathematical modeling, Sexual dimorphism, Speciation, Evolutionary genetics, Mathematical models, Evolutionary biology, and Altruistic behavior
- Language Label:
- English
- Page Start:
- e1002017
- Person:
- Dhole, Sumit, Goldberg, Emma E., Van Cleve, Jeremy, Brandvain, Yaniv, Yeh, D. Justin, Fitzpatrick, Courtney L., Servedio, Maria R., and Stern, Caitlin A.
- Rights Statement Label:
- In Copyright
- Source:
- jd473509s
1644. Unisexual and Heterosexual Meiotic Reproduction Generate Aneuploidy and Phenotypic Diversity De Novo in the Yeast Cryptococcus neoformans
- Title Tesim:
- Unisexual and Heterosexual Meiotic Reproduction Generate Aneuploidy and Phenotypic Diversity De Novo in the Yeast Cryptococcus neoformans
- Creator:
- Mieczkowski, Piotr, Feretzaki, Marianna, Dietrich, Fred S., Heitman, Joseph, Ni, Min, Li, Wenjun, and Floyd-Averette, Anna
- Date of publication:
- 2013
- Abstract Tesim:
- Aneuploidy is known to be deleterious and underlies several common human diseases, including cancer and genetic disorders such as trisomy 21 in Down's syndrome. In contrast, aneuploidy can also be advantageous and in fungi confers antifungal drug resistance and enables rapid adaptive evolution. We report here that sexual reproduction generates phenotypic and genotypic diversity in the human pathogenic yeast Cryptococcus neoformans, which is globally distributed and commonly infects individuals with compromised immunity, such as HIV/AIDS patients, causing life-threatening meningoencephalitis. C. neoformans has a defined a-α opposite sexual cycle; however, >99% of isolates are of the α mating type. Interestingly, α cells can undergo α-α unisexual reproduction, even involving genotypically identical cells. A central question is: Why would cells mate with themselves given that sex is costly and typically serves to admix preexisting genetic diversity from genetically divergent parents? In this study, we demonstrate that α-α unisexual reproduction frequently generates phenotypic diversity, and the majority of these variant progeny are aneuploid. Aneuploidy is responsible for the observed phenotypic changes, as chromosome loss restoring euploidy results in a wild-type phenotype. Other genetic changes, including diploidization, chromosome length polymorphisms, SNPs, and indels, were also generated. Phenotypic/genotypic changes were not observed following asexual mitotic reproduction. Aneuploidy was also detected in progeny from a-α opposite-sex congenic mating; thus, both homothallic and heterothallic sexual reproduction can generate phenotypic diversity de novo. Our study suggests that the ability to undergo unisexual reproduction may be an evolutionary strategy for eukaryotic microbial pathogens, enabling de novo genotypic and phenotypic plasticity and facilitating rapid adaptation to novel environments.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/5se7-ca58
- Identifier:
- Onescience id: c90deca351fd39161144bb42aae07843674a10a4, Publisher DOI: https://doi.org/10.1371/journal.pbio.1001653, PMID: 24058295, and PMCID: PMC3769227
- ISSN:
- 1545-7885 and 1544-9173
- Journal Issue:
- 9
- Journal Title:
- PLoS Biology
- Journal Volume:
- 11
- Keyword:
- Polymorphism, Restriction Fragment Length, Cryptococcus neoformans, Phenotype, Genotype, Polymorphism, Single Nucleotide, Meiosis, Drug Resistance, Fungal, Aneuploidy, Meningoencephalitis, Cryptococcosis, Genetic Variation, Fluconazole, Genes, Mating Type, Fungal, Reproduction, Asexual, and Antifungal Agents
- Language Label:
- English
- Page Start:
- e1001653
- Person:
- Mieczkowski, Piotr, Feretzaki, Marianna, Dietrich, Fred S., Heitman, Joseph, Ni, Min, Li, Wenjun, and Floyd-Averette, Anna
- Rights Statement Label:
- In Copyright
- Source:
- 0g354p17z
1645. The Case for Open Preprints in Biology
- Title Tesim:
- The Case for Open Preprints in Biology
- Creator:
- Desjardins-Proulx, Philippe, Ram, Karthik, White, Ethan P., Gravel, Dominique, Poisot, Timothée, and Adamson, Joel J.
- Date of publication:
- 2013
- Abstract Tesim:
- Biologists should submit their preprints to open servers, a practice common in mathematics and physics, to open and accelerate the scientific process.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/55ke-tr11
- Identifier:
- PMID: 23690752, Onescience id: b6af22ba787c6c092de302df425bddd056dcb434, Publisher DOI: https://doi.org/10.1371/journal.pbio.1001563, and PMCID: PMC3653830
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 5
- Journal Title:
- PLoS Biology
- Journal Volume:
- 11
- Keyword:
- Biologists, Scientists, Peer review, Public policy, Conservation science, Mathematical physics, Biophysics, and Science policy
- Language Label:
- English
- Page Start:
- e1001563
- Person:
- Desjardins-Proulx, Philippe, Ram, Karthik, White, Ethan P., Gravel, Dominique, Poisot, Timothée, and Adamson, Joel J.
- Rights Statement Label:
- In Copyright
- Source:
- qr46r7826
1646. In Silico Molecular Comparisons of C. elegans and Mammalian Pharmacology Identify Distinct Targets That Regulate Feeding
- Title Tesim:
- In Silico Molecular Comparisons of C. elegans and Mammalian Pharmacology Identify Distinct Targets That Regulate Feeding
- Creator:
- Shoichet, Brian K., Werb, Zena, Laggner, Christian, Mayer, Fahima, Bainton, Roland J., Keiser, Michael J., Ashrafi, Kaveh, Roth, Bryan L., Lemieux, George A., and Sassano, Maria F.
- Date of publication:
- 2013
- Abstract Tesim:
- Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/hdrf-bp38
- Identifier:
- PMID: 24260022, Onescience id: adae6d28e22d58ca5fcae7ec9fb78801c92d7dce, Publisher DOI: https://doi.org/10.1371/journal.pbio.1001712, and PMCID: PMC3833878
- ISSN:
- 1545-7885 and 1544-9173
- Journal Issue:
- 11
- Journal Title:
- PLoS Biology
- Journal Volume:
- 11
- Keyword:
- Small Molecule Libraries, Phenotype, Caenorhabditis elegans, SB 222200, Computer Simulation, Receptors, G-Protein-Coupled, Animals, Peristalsis, Drug Evaluation, Preclinical, Caenorhabditis elegans Proteins, Quinolines, Feeding Behavior, Pharynx, and Humans
- Language Label:
- English
- Page Start:
- e1001712
- Person:
- Shoichet, Brian K., Werb, Zena, Laggner, Christian, Mayer, Fahima, Bainton, Roland J., Keiser, Michael J., Ashrafi, Kaveh, Roth, Bryan L., Lemieux, George A., and Sassano, Maria F.
- Rights Statement Label:
- In Copyright
- Source:
- 8910k260s
1647. Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study
- Title Tesim:
- Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study
- Creator:
- Buyske, Steven, Thomas, Fridtjof, Dumitrescu, Logan, Heiss, Gerardo, Matise, Tara C., Kooperberg, Charles L., Ritchie, Marylyn D., Crawford, Dana C., Carlson, Christopher S., Peters, Ulrike, Eaton, Charles B., Fesinmeyer, Megan D., Hindorff, Lucia A., Le Marchand, Loic, Schumacher, Fredrick R., Carty, Cara, Duggan, David J., Young, Alicia, Franceschini, Nora, North, Kari E., Haiman, Christopher A., and Spencer, Kylee L.
- Date of publication:
- 2013
- Abstract Tesim:
- A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.Author SummaryThe number of known associations between human diseases and common genetic variants has grown dramatically in the past decade, most being identified in large-scale genetic studies of people of Western European origin. But because the frequencies of genetic variants can differ substantially between continental populations, it's important to assess how well these associations can be extended to populations with different continental ancestry. Are the correlations between genetic variants, disease endpoints, and risk factors consistent enough for genetic risk models to be reliably applied across different ancestries? Here we describe a systematic analysis of disease outcome and risk-factor–associated variants (tagSNPs) identified in European populations, in which we test whether the effect size of a tagSNP is consistent across six populations with significant non-European ancestry. We demonstrate that although nearly all such tagSNPs have effects in the same direction across all ancestries (i.e., variants associated with higher risk in Europeans will also be associated with higher risk in other populations), roughly a quarter of the variants tested have significantly different magnitude of effect (usually lower) in at least one non-European population. We therefore advise caution in the use of tagSNP-based genetic disease risk models in populations that have a different genetic ancestry from the population in which original associations were first made. We then show that this differential strength of association can be attributed to population-dependent variations in the correlation between tagSNPs and the variant that actually determines risk—the so-called functional variant. Risk models based on functional variants are therefore likely to be more robust than tagSNP-based models.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/kx40-7g59
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pbio.1001661, PMCID: PMC3775722, Onescience id: d50e204a47df89c816b69f090c7e327b43d2ee77, and PMID: 24068893
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 9
- Journal Title:
- PLoS Biology
- Journal Volume:
- 11
- Keyword:
- Genome-Wide Association Study, Gene Frequency, Genetic Predisposition to Disease, Diabetes Mellitus, Type 2, Asian Americans, Metagenomics, Genetic Variation, African Americans, Body Mass Index, Humans, Lipids, Indians, North American, Hispanic Americans, and European Continental Ancestry Group
- Language Label:
- English
- Page Start:
- e1001661
- Person:
- Buyske, Steven, Thomas, Fridtjof, Dumitrescu, Logan, Heiss, Gerardo, Matise, Tara C., Kooperberg, Charles L., Ritchie, Marylyn D., Crawford, Dana C., Carlson, Christopher S., Peters, Ulrike, Eaton, Charles B., Fesinmeyer, Megan D., Hindorff, Lucia A., Le Marchand, Loic, Schumacher, Fredrick R., Carty, Cara, Duggan, David J., Young, Alicia, Franceschini, Nora, North, Kari E., Haiman, Christopher A., and Spencer, Kylee L.
- Rights Statement Label:
- In Copyright
- Source:
- 0g354p16p
1648. A User's Guide to the Encyclopedia of DNA Elements (ENCODE)
- Title Tesim:
- A User's Guide to the Encyclopedia of DNA Elements (ENCODE)
- Creator:
- The ENCODE Project Consortium
- Date of publication:
- 2011
- Abstract Tesim:
- The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/b1kd-vb30
- Identifier:
- Onescience id: 19eea27789302cb3711d6f2a6adb6459ee9cad75, PMID: 21526222, PMCID: PMC3079585, and Publisher DOI: https://doi.org/10.1371/journal.pbio.1001046
- ISSN:
- 1545-7885 and 1544-9173
- Journal Issue:
- 4
- Journal Title:
- PLoS Biology
- Journal Volume:
- 9
- Keyword:
- RNA-Binding Proteins/metabolism, Nucleic Acid, Humans, Internet, Genetic, Base Sequence, Chromatin/metabolism, Quality Control, RNA, DNA-Binding Proteins/metabolism, Databases, Human, RNA-Binding Proteins/genetics, Models, Gene Components, DNA Methylation, Genome, Conserved Sequence, DNA-Binding Proteins/genetics, Gene Expression Regulation, and Messenger/genetics
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Page Start:
- e1001046
- Person:
- The ENCODE Project Consortium
- Rights Statement Label:
- In Copyright
- Source:
- g445cm90n
1649. CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium
- Title Tesim:
- CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium
- Creator:
- Boucher, Richard C., Dang, Yan Li, Yan, Yu, Vogel, Leatrice N., Gabriel, Sherif E., Burkett, Susan, McKay, Tristan, Mengos, April, Zhang, Liqun, Collins, Peter L., Button, Brian, Skiadopoulos, Mario H., and Pickles, Raymond J.
- Date of publication:
- 2009
- Abstract Tesim:
- Delivering CFTR to ciliated cells of cystic fibrosis (CF) patients fully restores ion and fluid transport to the lumenal surface of airway epithelium and returns mucus transport rates to those of non-CF airways.Dysfunction of CFTR in cystic fibrosis (CF) airway epithelium perturbs the normal regulation of ion transport, leading to a reduced volume of airway surface liquid (ASL), mucus dehydration, decreased mucus transport, and mucus plugging of the airways. CFTR is normally expressed in ciliated epithelial cells of the surface and submucosal gland ductal epithelium and submucosal gland acinar cells. Critical questions for the development of gene transfer strategies for CF airway disease are what airway regions require CFTR function and how many epithelial cells require CFTR expression to restore normal ASL volume regulation and mucus transport to CF airway epithelium? An in vitro model of human CF ciliated surface airway epithelium (CF HAE) was used to test whether a human parainfluenza virus (PIV) vector engineered to express CFTR (PIVCFTR) could deliver sufficient CFTR to CF HAE to restore mucus transport, thus correcting the CF phenotype. PIVCFTR delivered CFTR to >60% of airway surface epithelial cells and expressed CFTR protein in CF HAE approximately 100-fold over endogenous levels in non-CF HAE. This efficiency of CFTR delivery fully corrected the basic bioelectric defects of Cl− and Na+ epithelial ion transport and restored ASL volume regulation and mucus transport to levels approaching those of non-CF HAE. To determine the numbers of CF HAE surface epithelial cells required to express CFTR for restoration of mucus transport to normal levels, different amounts of PIVCFTR were used to express CFTR in 3%–65% of the surface epithelial cells of CF HAE and correlated to increasing ASL volumes and mucus transport rates. These data demonstrate for the first time, to our knowledge, that restoration of normal mucus transport rates in CF HAE was achieved after CFTR delivery to 25% of surface epithelial cells. In vivo experimentation in appropriate models will be required to determine what level of mucus transport will afford clinical benefit to CF patients, but we predict that a future goal for corrective gene transfer to the CF human airways in vivo would attempt to target at least 25% of surface epithelial cells to achieve mucus transport rates comparable to those in non-CF airways.Author SummaryThe ciliated epithelium that lines the conducting airways of the lung normally functions to transport hydrated mucus secretions out of the airways to maintain respiratory sterility. Cystic fibrosis (CF) lung disease results from reduced airway surface hydration leading to decreased mucus clearance that precipitates bacterial infection and progressive obstructive lung disease. CF is a genetic disease, and the mutant protein is a chloride ion channel (CFTR) that normally regulates ion and fluid transport on the airway surface. Restoration of corrected CFTR function to the airway epithelium of CF patients by delivering a new CFTR gene to airway epithelial cells has long been envisioned as a therapeutic strategy for CF lung disease. Towards this goal, we use a novel viral vector to deliver CFTR to a culture model that represents the ciliated airway epithelium of CF patients and show that this strategy restores airway surface hydration and mucus transport to levels of that in non-CF individuals. This study demonstrates efficient and efficacious CFTR delivery to CF ciliated airway epithelium and that CFTR delivered to approximately 25% of the surface epithelial cells restores normal levels of airway surface hydration and mucus transport. These studies serve as a benchmark for the efficiency of CFTR gene delivery to CF airways for future CF gene therapy studies in vivo.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/shw8-yj37
- Identifier:
- PMID: 19621064, Publisher DOI: https://doi.org/10.1371/journal.pbio.1000155, PMCID: PMC2705187, and Onescience id: 6ebb7ec3d463af3438028d2d7ac714af50f90b21
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 7
- Journal Title:
- PLoS Biology
- Journal Volume:
- 7
- Keyword:
- Gene Expression, Gene Transfer Techniques, Chlorides, Cells, Cultured, Biological Transport, Microscopy, Fluorescence, Cystic Fibrosis Transmembrane Conductance Regulator, Epithelial Cells, Cystic Fibrosis, Immunohistochemistry, Green Fluorescent Proteins, Analysis of Variance, Genetic Vectors, and Humans
- Language Label:
- English
- Page Start:
- e1000155
- Person:
- Boucher, Richard C., Dang, Yan Li, Yan, Yu, Vogel, Leatrice N., Gabriel, Sherif E., Burkett, Susan, McKay, Tristan, Mengos, April, Zhang, Liqun, Collins, Peter L., Button, Brian, Skiadopoulos, Mario H., and Pickles, Raymond J.
- Rights Statement Label:
- In Copyright
- Source:
- g158br462
1650. Bringing Molecular Tools into Environmental Resource Management: Untangling the Molecules to Policy Pathway
- Title Tesim:
- Bringing Molecular Tools into Environmental Resource Management: Untangling the Molecules to Policy Pathway
- Creator:
- Carlsson, Jens, Sagarin, Raphael, Freshwater, Wilson, Duval, Michelle, Wynne, Bennett, Litaker, Wayne, Schultz, Tom, Godfrey, Matthew H, Muñoz, Roldan, and Noble, Rachel
- Date of publication:
- 2009
- Abstract Tesim:
- New advances in molecular biology can be invaluable tools in resource management, but they are best incorporated through a collaborative process with managers who understand the most pressing questions, practical limitations, and political constraints.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/pcgv-ge67
- Identifier:
- PMID: 19338385, Onescience id: 369550073df894a25a2f454e4ea5c6bf38353cff, PMCID: PMC2661961, and Publisher DOI: https://doi.org/10.1371/journal.pbio.1000069
- ISSN:
- 1545-7885 and 1544-9173
- Journal Issue:
- 3
- Journal Title:
- PLoS Biology
- Journal Volume:
- 7
- Keyword:
- Shellfish, Water Microbiology, Crassostrea, Public Policy, Humans, Environmental Monitoring, Policy Making, Water Pollutants, Genetic Techniques, Conservation of Natural Resources, Politics, Environment, and Animals
- Language Label:
- English
- Page Start:
- e1000069
- Person:
- Carlsson, Jens, Sagarin, Raphael, Freshwater, Wilson, Duval, Michelle, Wynne, Bennett, Litaker, Wayne, Schultz, Tom, Godfrey, Matthew H, Muñoz, Roldan, and Noble, Rachel
- Rights Statement Label:
- In Copyright
- Source:
- t148fr02r
Collection Details
- Total items
-
2112
- Size
-
unknown
- Date created
-
February 2, 2022