Search

Your search keyword '"Kominsky, Douglas"' showing total 222 results
Start Over Author "Kominsky, Douglas"
222 results on '"Kominsky, Douglas"'

2. ELP1, the Gene Mutated in Familial Dysautonomia, Is Required for Normal Enteric Nervous System Development and Maintenance and for Gut Epithelium Homeostasis.

Author

Chaverra, Marta, Cheney, Alexandra M., Scheel, Alpha, Miller, Alessa, George, Lynn, Schultz, Anastasia, Henningsen, Katelyn, Kominsky, Douglas, Walk, Heather, Kennedy, William R., Kaufmann, Horacio, Walk, Seth, Copié, Valérie, and Lefcort, Frances

Subjects
ENTERIC nervous system, DYSAUTONOMIA, INTESTINAL mucosa, DOPAMINERGIC neurons, EMBRYOLOGY
Abstract

Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in the ELP1 gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only is Elp1 required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in which Elp1 was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion of Elp1 exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

17. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia

Author

Eckle, Tobias, Hartmann, Katherine, Bonney, Stephanie, Reithel, Susan, Mittelbronn, Michel, Walker, Lori A., Lowes, Brian D., Han, Jun, Borchers, Christoph H., Buttrick, Peter M., Kominsky, Douglas J., Colgan, Sean P., and Eltzschig, Holger K.

Subjects
Glucose metabolism -- Physiological aspects -- Genetic aspects -- Research, Myocardial ischemia -- Complications and side effects -- Genetic aspects -- Research, DNA binding proteins -- Physiological aspects -- Research, Biological sciences, Health
Abstract

Adenosine signaling has been implicated in cardiac adaptation to limited oxygen availability. In a wide search for adenosine receptor A2b (Adora2b)-elicited cardioadaptive responses, we identified the circadian rhythm protein period 2 (Per2) as an Adora2b target. Adora2b signaling led to Per2 stabilization during myocardial ischemia, and in this setting, [Per2.sup.-/-] mice had larger infarct sizes compared to wild-type mice and loss of the cardioprotection conferred by ischemic preconditioning. Metabolic studies uncovered a limited ability of ischemic hearts in [Per2.sup.-/-] mice to use carbohydrates for oxygen-efficient glycolysis. This impairment was caused by a failure to stabilize hypoxia-inducible factor-1a (Hif-1a). Moreover, stabilization of Per2 in the heart by exposing mice to intense light resulted in the transcriptional induction of glycolytic enzymes and Per2-dependent cardioprotection from ischemia. Together, these studies identify adenosine-elicited stabilization of Per2 in the control of HIF-dependent cardiac metabolism and ischemia tolerance and implicate Per2 stabilization as a potential new strategy for treating myocardial ischemia., Metabolic adaptation during environmental stress is currently an area of intense investigation because of the potential implications of metabolic alterations in human disease (1), (2). For example, myocardial ischemia leads [...]

Published
2012
Full Text
View/download PDF

18. Transmigrating Neutrophils Shape the Mucosal Microenvironment through Localized Oxygen Depletion to Influence Resolution of Inflammation

Author

Campbell, Eric L., Bruyninckx, Walter J., Kelly, Caleb J., Glover, Louise E., McNamee, Eóin N., Bowers, Brittelle E., Bayless, Amanda J., Scully, Melanie, Saeedi, Bejan J., Golden-Mason, Lucy, Ehrentraut, Stefan F., Curtis, Valerie F., Burgess, Adrianne, Garvey, John F., Sorensen, Amber, Nemenoff, Raphael, Jedlicka, Paul, Taylor, Cormac T., Kominsky, Douglas J., and Colgan, Sean P.

Published
2014
Full Text
View/download PDF

22. Genetic and biochemical basis for viability of yeast lacking mitochondrial genomes

Author

Kominsky, Douglas J., Brownson, Mary P., Updike, Dustin L., and Thorsness, Peter E.

Subjects
Genetic research, Yeast fungi -- Genetic aspects, Biological sciences
Abstract

Yme1p, an ATP-dependent protease localized in the mitochondrial inner membrane, is required for the growth of yeast lacking an intact mitochondrial genome. Specific dominant mutations in the genes encoding the [alpha]- and [gamma]-subunits of the mitochondrial [F.sub.1][F.sub.0]-ATPase suppress the slow-growth phenotype of yeast that simultaneously lack Yme1p and mitochondrial DNA. [F.sub.1][F.sub.0]-ATPase activity is reduced in yeast lacking Yme1p and is restored in yme1 strains bearing suppressing mutations in [F.sub.1]-ATPasc structural genes. Mitochondria isolated from yme1 yeast generated a membrane potential upon the addition of succinate, but unlike mitochondria isolated either from wild-type yeast or from yeast bearing yme1 and a suppressing mutation, were unable to generate a membrane potential upon the addition of ATP. Nuclear-encoded [F.sub.0] subunits accumulate in yme1 yeast lacking mitochondrial DNA; however, deletion of genes encoding those subunits did not suppress the requirement of yme1 yeast for intact mitochondrial DNA. In contrast, deletion of INH1, which encodes an inhibitor of the [F.sub.1][F.sub.0]-ATPase, partially suppressed the growth defect of yme1 yeast lacking mitochondrial DNA. We conclude that Yme1p is in part responsible for assuring sufficient [F.sub.1][F.sub.0]-ATPase activity to generate a membrane potential in mitochondria lacking mitochondrial DNA and propose that Yme1p accomplishes this by catalyzing the turnover of protein inhibitors of the [F.sub.1][F.sub.0]-ATPase.

Published
2002

26. Slug and Snail have differential effects in directing colonic epithelial wound healing and partially mediate the restitutive effects of butyrate

Author

Swain, Steve D., primary, Grifka-Walk, Heather N., additional, Gripentrog, Jeannie, additional, Lehmann, Margaret, additional, Deuling, Benjamin, additional, Jenkins, Brittany, additional, Liss, Hailey, additional, Blaseg, Nathan, additional, Bimczok, Diane, additional, and Kominsky, Douglas J., additional

Published
2019
Full Text
View/download PDF

27. Oral vitamin B12 supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting Bacteroides in C57BL/6 mice

Author

Kelly, Caleb J, primary, Alexeev, Erica E, additional, Farb, Linda, additional, Vickery, Thad W, additional, Zheng, Leon, additional, Eric L, Campbell, additional, Kitzenberg, David A, additional, Battista, Kayla D, additional, Kominsky, Douglas J, additional, Robertson, Charles E, additional, Frank, Daniel N, additional, Stabler, Sally P, additional, and Colgan, Sean P, additional

Published
2019
Full Text
View/download PDF

33. Expression of the Saccharomyces cerevisiae Gene YME1 in the Petite-Negative Yeast Schizosaccharomyces pombe Converts It to Petite-Positive

Author

Kominsky, Douglas J. and Thorsness, Peter E.

Subjects
Brewer's yeast -- Research, Gene expression -- Research, Gene mutations -- Research, Biological sciences
Abstract

Organisms that can grow without mitochondrial DNA are referred to as 'petite-positive' and those that are inviable in the absence of mitochondrial DNA are termed 'petite-negative.' The petite-positive yeast Saccharomyces cerevisiae can be converted to a petite-negative yeast by inactivation of Ymelp, an ATP- and metal-dependent protease associated with the inner mitochondrial membrane. Suppression of this ymel phenotype can occur by virtue of dominant mutations in the [Alpha]- and [Gamma]-subunits of mitochondrial ATP synthase. These mutations are similar or identical to those occurring in the same subunits of the same enzyme that converts the petite-negative yeast Kluyveromyces lactis to petite-positive. Expression of YME1 in the petite-negative yeast Schizosaccharomyces pombe converts this yeast to petite-positive. No sequence closely related to YME1 was found by DNA-blot hybridization to S. pombe or K. lactis genomic DNA, and no antigenically related proteins were found in mitochondrial extracts of S. pombe probed with antisera directed against Yme1p. Mutations that block the formation of the [F.sub.1] component of mitochondrial ATP synthase are also petite-negative. Thus, the [F.sub.1] complex has an essential activity in cells lacking mitochondrial DNA and Ymelp can mediate that activity, even in heterologous systems.

Published
2000

34. Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation

Author

Ehrentraut, Stefan F., primary, Curtis, Valerie F., additional, Wang, Ruth X., additional, Saeedi, Bejan J., additional, Ehrentraut, Heidi, additional, Onyiah, Joseph C., additional, Kelly, Caleb J., additional, Campbell, Eric L., additional, Glover, Louise E., additional, Kominsky, Douglas J., additional, and Colgan, Sean P., additional

Published
2016
Full Text
View/download PDF

35. G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ

Author

Frasch, S. Courtney, primary, McNamee, Eóin N., additional, Kominsky, Douglas, additional, Jedlicka, Paul, additional, Jakubzick, Claudia, additional, Zemski Berry, Karin, additional, Mack, Matthias, additional, Furuta, Glenn T., additional, Lee, James J., additional, Henson, Peter M., additional, Colgan, Sean P., additional, and Bratton, Donna L., additional

Published
2016
Full Text
View/download PDF

41. Oral vitamin B12supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting Bacteroidesin C57BL/6 mice

Author

Kelly, Caleb J, Alexeev, Erica E, Farb, Linda, Vickery, Thad W, Zheng, Leon, Eric L, Campbell, Kitzenberg, David A, Battista, Kayla D, Kominsky, Douglas J, Robertson, Charles E, Frank, Daniel N, Stabler, Sally P, and Colgan, Sean P

Abstract

ABSTRACTVitamin B12is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B12supplements are largely unabsorbed and reach the distal gut where they are available to interact with the microbiota. The aim of this study was to determine if oral B12supplementation in mice alters 1) the concentration of B12and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis. C57BL/6 mice (up to 24 animals/group) were supplemented with oral 3.94 µg/ml cyanocobalamin (B12), a dose selected to approximate a single 5 mg supplement for a human. Active vitamin B12(cobalamin), and four B12-analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba, CN-Cbi) were analyzed in cecal and fecal contents using liquid chromatography/mass spectrometry (LC/MS), in parallel with evaluation of fecal microbiota, cecal SCFA, and susceptibility to dextran sodium sulfate (DSS) colitis. At baseline, active B12was a minor constituent of overall cecal (0.86%) and fecal (0.44%) corrinoid. Oral B12supplementation increased active B12at distal sites by >130-fold (cecal B12increased from 0.08 to 10.60 ng/mg, fecal B12increased from 0.06 to 7.81 ng/ml) and reduced microbe-derived fecal corrinoid analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba). Oral B12had no effect on cecal SCFA. Microbial diversity was unaffected by this intervention, however a selective decrease in Bacteroideswas observed with B12treatment. Lastly, no difference in markers of DSS-induced colitis were detected with B12treatment.

Published
2019
Full Text
View/download PDF

42. Identification of Hypoxia-induced Metabolic Changes in Human Intestinal Epithelial Cells

Author

Ladak, Adam, Kominsky, Douglas, Colgan, Sean, and Jonscher, Karen

Subjects
Scientific Poster Abstracts
Abstract

BACKGROUND: Inflammatory Bowel Disease (IBD) is an intestinal inflammatory process resulting in abnormal gut barrier function; reduced oxygen delivery within the epithelium has been correlated with shifts in tissue metabolism. The goal of this study was to investigate the utility of high-resolution mass spectrometry coupled with full-coverage fragmentation for analysis of metabolite changes induced by hypoxia. METHODS: T84 intestinal epithelial cells were cultured and exposed to either 24 hours of hypoxia (10% oxygen) or normoxia. Cells were lysed and metabolites extracted with ice-cold methanol. Two microliters (0.06%) of sample were injected onto an Acquity UPLC coupled to a Waters Synapt G2-S Q-TOF in high-resolution mode utilizing MSE fragmentation. Six replicates of each sample, as well as a pooled sample, were analyzed in positive and negative ion mode over a 10 minute gradient. RESULTS: Over 2,000 features, consisting of exact mass, abundance and retention time, were identified in each sample with MarkerLynx XS and search of the built-in database. Data were submitted to ChromaLynx for determination of elemental composition. High-energy fragmentation data were utilized by MassFragment to validate candidate molecular structures. Principal components analysis showed differential clustering of the hypoxia, normoxia and pooled samples and an S-plot identified potential markers that were prominent in hypoxia or normoxia. Metabolites of increased abundance in hypoxic samples included glutathione and LysoPC(18:1(9Z)), as well as a compound of m/z 560.3109; in negative ion mode we identified pyroglutamic acid and citric acid, as well as 6 other compounds. Metabolites increased in normoxia included indoleacrylic acid, N1,N12-diacetylspermine and compounds with m/z 288.2890 and 316.3203; in negative ion mode we identified 16-dehydroprogesterone and 3 other compounds. Unidentified compounds, potentially resulting from adduction of Na or NH4, are under investigation. CONCLUSIONS: The Synapt G2-S provided a highly sensitive and rapid method for identification of metabolite markers reflective of hypoxia.

Published
2012

43. Retinoic Acid Attenuates Ileitis by Restoring the Balance between T-Helper 17 and T

Author

Collins, Colm B., Aherne, Carol M., Kominsky, Douglas, McNamee, Eóin N., Lebsack, Matthew D.P., Eltzschig, Holger, Jedlicka, Paul, and Rivera-Nieves, Jesús

Subjects
Mice, Knockout, Forkhead Transcription Factors, Mice, Inbred Strains, Tretinoin, Dendritic Cells, Ileitis, T-Lymphocytes, Regulatory, Article, Coculture Techniques, Mice, Inbred C57BL, Disease Models, Animal, Mice, Antigens, CD, Animals, Cytokines, Th17 Cells, Integrin alpha Chains, Cells, Cultured, Cell Proliferation
Abstract

Retinoic acid (RA), produced by intestinal epithelial cells (IECs) and dendritic cells (DCs) promotes the induction of regulatory T cells (Tregs) and decreases the induction of T-helper (Th)17 cells.We studied the roles of RA in mice that overproduce tumor necrosis factor (TNF) and develop chronic ileitis (TNF_ARE mice). We assessed the frequency and function of CD103+ DCs, Th17 cells, and Tregs by flow cytometry, and we measured expression of cytokines and retinaldehyde dehydrogenase (RALDH) enzymes in ileum samples, DCs, and IECs by real-time polymerase chain reaction. We quantified RA by electrochemical analysis and examined the effect of RA supplementation on TNF-induced ileitis using histologic, coculture, and suppression assays and flow cytometry.Numbers of CD103+ DCs decreased in the inflamed ilea of mice with chronic disease; RA synthetic machinery (RALDH1,2) was down-regulated. Nevertheless, the proportion of CD4+, CD25+, FoxP3+ Tregs increased, indicating an alternate source for RA. IECs responded to reduced levels of RA by up-regulating RALDH3 in vivo and in vitro. Net tissue levels of RA remained lower in TNF+ARE than wild-type mice, indicating that epithelial up-regulation of RALDH3 could not maintain adequate concentrations of RA, probably because of loss of IEC mass. RA supplementation significantly attenuated disease by increasing the number and function of CD103+ DCs and Tregs and reducing Th17 cells.Reduced levels of RA appear to induce IECs to up-regulate synthesis of RA. RA supplementation attenuates ileitis through its effects on CD103+ DCs, Tregs, and Th17 cells. RA supplementation might offer therapeutic benefit in Crohn's disease.

Published
2011

44. HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity

Author

Saeedi, Bejan J., primary, Kao, Daniel J., additional, Kitzenberg, David A., additional, Dobrinskikh, Evgenia, additional, Schwisow, Kayla D., additional, Masterson, Joanne C., additional, Kendrick, Agnieszka A., additional, Kelly, Caleb J., additional, Bayless, Amanda J., additional, Kominsky, Douglas J., additional, Campbell, Eric L., additional, Kuhn, Kristine A., additional, Furuta, Glenn T., additional, Colgan, Sean P., additional, and Glover, Louise E., additional

Published
2015
Full Text
View/download PDF

45. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function

Author

Kelly, Caleb J., primary, Zheng, Leon, additional, Campbell, Eric L., additional, Saeedi, Bejan, additional, Scholz, Carsten C., additional, Bayless, Amanda J., additional, Wilson, Kelly E., additional, Glover, Louise E., additional, Kominsky, Douglas J., additional, Magnuson, Aaron, additional, Weir, Tiffany L., additional, Ehrentraut, Stefan F., additional, Pickel, Christina, additional, Kuhn, Kristine A., additional, Lanis, Jordi M., additional, Nguyen, Vu, additional, Taylor, Cormac T., additional, and Colgan, Sean P., additional

Published
2015
Full Text
View/download PDF

47. Microbe‐Host Crosstalk between Short‐Chain Fatty Acids and Intestinal Epithelial HIF Provides a New Mechanism to Augment Tissue Barrier Function

Author

Zheng, Leon, primary, Kelly, Caleb, additional, Campbell, Eric, additional, Saeedi, Bejan, additional, Scholz, Carsten, additional, Bayless, Amanda, additional, Wilson, Kelly, additional, Glover, Louise, additional, Kominsky, Douglas, additional, Magnuson, Aaron, additional, Weir, Tiffany, additional, Ehrentraut, Stefan, additional, Nguyen, Vu, additional, Taylor, Cormac, additional, and Colgan, Sean, additional

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results