Comprehensive Map of Molecules Implicated in Obesity.

PLoS One. 2016;11(2):e0146759

Authors: Jagannadham J, Jaiswal HK, Agrawal S, Rawal K

Abstract
Obesity is a global epidemic affecting over 1.5 billion people and is one of the risk factors for several diseases such as type 2 diabetes mellitus and hypertension. We have constructed a comprehensive map of the molecules reported to be implicated in obesity. A deep curation strategy was complemented by a novel semi-automated text mining system in order to screen 1,000 full-length research articles and over 90,000 abstracts that are relevant to obesity. We obtain a scale free network of 804 nodes and 971 edges, composed of 510 proteins, 115 genes, 62 complexes, 23 RNA molecules, 83 simple molecules, 3 phenotype and 3 drugs in "bow-tie" architecture. We classify this network into 5 modules and identify new links between the recently discovered fat mass and obesity associated FTO gene with well studied examples such as insulin and leptin. We further built an automated docking pipeline to dock orlistat as well as other drugs against the 24,000 proteins in the human structural proteome to explain the therapeutics and side effects at a network level. Based upon our experiments, we propose that therapeutic effect comes through the binding of one drug with several molecules in target network, and the binding propensity is both statistically significant and different in comparison with any other part of human structural proteome.

PMID: 26886906 [PubMed - indexed for MEDLINE]

Detecting themes of public concern: a text mining analysis of the Centers for Disease Control and Prevention's Ebola live Twitter chat.

Am J Infect Control. 2015 Oct 1;43(10):1109-11

Authors: Lazard AJ, Scheinfeld E, Bernhardt JM, Wilcox GB, Suran M

Abstract
A diagnosis of Ebola on US soil triggered widespread panic. In response, the Centers for Disease Control and Prevention held a live Twitter chat to address public concerns. This study applied a textual analytics method to reveal insights from these tweets that can inform communication strategies. User-generated tweets were collected, sorted, and analyzed to reveal major themes. The public was concerned with symptoms and lifespan of the virus, disease transfer and contraction, safe travel, and protection of one's body.

PMID: 26138998 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/20

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Systems Biology"[Title/Abstract] AND ("2005/01/01"[PDAT] : "3000"[PDAT])

These pubmed results were generated on 2016/07/20

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Tumor deconstruction as a tool for advanced drug screening and repositioning.

Pharmacol Res. 2016 Jul 15;

Authors: Naik RR, Luo T, Kohandel M, Bapat SA

Abstract
A major focus of contemporary drug screening strategies is the identification of novel anticancer compounds, which often results in underutilization of resources. Current drug evaluation involves in vivo tumor (xenograft) regression as proof-of-principle for cytotoxicity (POC). However, this end-point lacks any assessment of drug resistance of the residual tumor and its capability to establish refractory and/or recurrent disease, which would represent more appropriate indicators of therapeutic failure. We have recently developed a flow cytometry-based approach for the analyses of intra-tumor cellular heterogeneity across stem cell hierarchies, genetic instability and differential cell cycling fractions, which can potentially be predictive of refractory disease and tumor relapse. Iterating this approach after initial POC screening in the drug discovery pipeline would have a great impact in terms of precision of drug evaluation, design of optimal drug combinations and/or drug repositioning. In this perspective, we highlight how through embracing of a comprehensive, informative and analytical assessment of the cellular content of residual tumors, the fidelity and statistical robustness of preclinical drug discovery can be greatly improved.

PMID: 27431330 [PubMed - as supplied by publisher]

Repurposing old drugs to chemoprevention: the case of metformin.

Semin Oncol. 2016 Feb;43(1):123-33

Authors: Heckman-Stoddard BM, Gandini S, Puntoni M, Dunn BK, DeCensi A, Szabo E

Abstract
Multiple epidemiologic studies have documented an association between the anti-diabetic agent metformin and reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models or more recent epidemiological studies. The purpose of this paper is to examine metformin's chemopreventive potential by reviewing relevant mechanisms of action, preclinical evidence of efficacy, updated epidemiologic evidence after correction for potential biases and confounders, and recently completed and ongoing clinical trials. Although repurposing drugs with well described mechanisms of action and safety profiles is an appealing strategy for cancer prevention, there is no substitute for well executed late phase clinical trials to define efficacy and populations that are most likely to benefit from an intervention.

PMID: 26970131 [PubMed - indexed for MEDLINE]

Regulation of Inflammation by IL-17A and IL-17F Modulates Non-Alcoholic Fatty Liver Disease Pathogenesis.

PLoS One. 2016;11(2):e0149783

Authors: Giles DA, Moreno-Fernandez ME, Stankiewicz TE, Cappelletti M, Huppert SS, Iwakura Y, Dong C, Shanmukhappa SK, Divanovic S

Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)--a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction--and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.

PMID: 26895034 [PubMed - indexed for MEDLINE]

Publishing FAIR Data: An Exemplar Methodology Utilizing PHI-Base.

Front Plant Sci. 2016;7:641

Authors: Rodríguez-Iglesias A, Rodríguez-González A, Irvine AG, Sesma A, Urban M, Hammond-Kosack KE, Wilkinson MD

Abstract
Pathogen-Host interaction data is core to our understanding of disease processes and their molecular/genetic bases. Facile access to such core data is particularly important for the plant sciences, where individual genetic and phenotypic observations have the added complexity of being dispersed over a wide diversity of plant species vs. the relatively fewer host species of interest to biomedical researchers. Recently, an international initiative interested in scholarly data publishing proposed that all scientific data should be "FAIR"-Findable, Accessible, Interoperable, and Reusable. In this work, we describe the process of migrating a database of notable relevance to the plant sciences-the Pathogen-Host Interaction Database (PHI-base)-to a form that conforms to each of the FAIR Principles. We discuss the technical and architectural decisions, and the migration pathway, including observations of the difficulty and/or fidelity of each step. We examine how multiple FAIR principles can be addressed simultaneously through careful design decisions, including making data FAIR for both humans and machines with minimal duplication of effort. We note how FAIR data publishing involves more than data reformatting, requiring features beyond those exhibited by most life science Semantic Web or Linked Data resources. We explore the value-added by completing this FAIR data transformation, and then test the result through integrative questions that could not easily be asked over traditional Web-based data resources. Finally, we demonstrate the utility of providing explicit and reliable access to provenance information, which we argue enhances citation rates by encouraging and facilitating transparent scholarly reuse of these valuable data holdings.

PMID: 27433158 [PubMed]

An ensemble method for extracting adverse drug events from social media.

Artif Intell Med. 2016 Jun;70:62-76

Authors: Liu J, Zhao S, Zhang X

Abstract
OBJECTIVE: Because adverse drug events (ADEs) are a serious health problem and a leading cause of death, it is of vital importance to identify them correctly and in a timely manner. With the development of Web 2.0, social media has become a large data source for information on ADEs. The objective of this study is to develop a relation extraction system that uses natural language processing techniques to effectively distinguish between ADEs and non-ADEs in informal text on social media.
METHODS AND MATERIALS: We develop a feature-based approach that utilizes various lexical, syntactic, and semantic features. Information-gain-based feature selection is performed to address high-dimensional features. Then, we evaluate the effectiveness of four well-known kernel-based approaches (i.e., subset tree kernel, tree kernel, shortest dependency path kernel, and all-paths graph kernel) and several ensembles that are generated by adopting different combination methods (i.e., majority voting, weighted averaging, and stacked generalization). All of the approaches are tested using three data sets: two health-related discussion forums and one general social networking site (i.e., Twitter).
RESULTS: When investigating the contribution of each feature subset, the feature-based approach attains the best area under the receiver operating characteristics curve (AUC) values, which are 78.6%, 72.2%, and 79.2% on the three data sets. When individual methods are used, we attain the best AUC values of 82.1%, 73.2%, and 77.0% using the subset tree kernel, shortest dependency path kernel, and feature-based approach on the three data sets, respectively. When using classifier ensembles, we achieve the best AUC values of 84.5%, 77.3%, and 84.5% on the three data sets, outperforming the baselines.
CONCLUSIONS: Our experimental results indicate that ADE extraction from social media can benefit from feature selection. With respect to the effectiveness of different feature subsets, lexical features and semantic features can enhance the ADE extraction capability. Kernel-based approaches, which can stay away from the feature sparsity issue, are qualified to address the ADE extraction problem. Combining different individual classifiers using suitable combination methods can further enhance the ADE extraction effectiveness.

PMID: 27431037 [PubMed - in process]

CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects.

J Clin Pharmacol. 2016 Jul 19;

Authors: Zhu L, Brüggemann RJ, Uy J, Colbers A, Hruska MW, Chung E, Sims K, Vakkalagadda B, Xu X, van Schaik RH, Burger DM, Bertz RJ

Abstract
Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and to a lesser extent by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added-on to ritonavir-boosted atazanavir in both CYP2C19 extensive metabolizer (EM) and poor metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3 followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. Upon coadministration, voriconazole AUC and Cmin decreased by 33% (90% CI = 22-42%) and 39% (90% CI = 28-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4- (90% CI = 3.6-5.4) and 5.6-fold (90% CI = 4.5-7.0), respectively, in PMs. Adding voriconazole resulted in a 20-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposures were generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination. This article is protected by copyright. All rights reserved.

PMID: 27432796 [PubMed - as supplied by publisher]

Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

Pharmacogenomics J. 2016 Jul 19;

Authors: Daniels MA, Kan C, Willmes DM, Ismail K, Pistrosch F, Hopkins D, Mingrone G, Bornstein SR, Birkenfeld AL

Abstract
Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.The Pharmacogenomics Journal advance online publication, 19 July 2016; doi:10.1038/tpj.2016.54.

PMID: 27432533 [PubMed - as supplied by publisher]

Long Non-coding RNA BGas Regulates the Cystic Fibrosis Transmembrane Conductance Regulator.

Mol Ther. 2016 Jul 19;

Authors: Saayman SM, Ackley A, Burdach J, Clemson M, Gruenert DC, Tachikawa K, Chivukula P, Weinberg MS, Morris KV

Abstract
Cystic fibrosis (CF) is a life-shortening genetic disease. The root cause of CF is heritable recessive mutations that affect the cystic fibrosis transmembrance conductance regulator (CFTR) gene and the subsequent expression and activity of encoded ion channels at the cell surface. We show that CFTR is regulated transcriptionally by the actions of a novel long noncoding RNA (lncRNA), designated as BGas, that emanates from intron 11 of the CFTR gene and is expressed in the antisense orientation relative to the protein coding sense strand. We find that BGas functions in concert with several proteins including HMGA1, HMGB1, and WIBG to modulate the local chromatin and DNA architecture of intron 11 of the CFTR gene and thereby affects transcription. Suppression of BGas or its associated proteins results in a gain of both CFTR expression and chloride ion function. The observations described here highlight a previously underappreciated mechanism of transcriptional control and suggest that BGas may serve as a therapeutic target for specifically activating expression of CFTR.Molecular Therapy (2016); doi:10.1038/mt.2016.112.

PMID: 27434588 [PubMed - as supplied by publisher]

Bile signalling promotes chronic respiratory infections and antibiotic tolerance.

Sci Rep. 2016;6:29768

Authors: Reen FJ, Flynn S, Woods DF, Dunphy N, Chróinín MN, Mullane D, Stick S, Adams C, O'Gara F

Abstract
Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease.

PMID: 27432520 [PubMed - in process]

One Center's Guide to Outpatient Management of Pediatric Cystic Fibrosis Acute Pulmonary Exacerbation.

Clin Med Insights Pediatr. 2016;10:57-65

Authors: Muirhead CA, Sanford JN, McCullar BG, Nolt D, MacDonald KD

Abstract
Cystic fibrosis (CF) is a chronic disorder characterized by acute pulmonary exacerbations that comprise increased cough, chest congestion, increased mucus production, shortness of breath, weight loss, and fatigue. Typically, severe episodes are treated in the inpatient setting and include intravenous antimicrobials, airway clearance therapy, and nutritional support. Children with less-severe findings can often be managed as outpatients with oral antimicrobials and increased airway clearance therapy at home without visiting the specialty CF center to begin treatment. Selection of specific antimicrobial agents is dependent on pathogens found in surveillance culture, activity of an agent in patients with CF, and the unique physiology of these patients. In this pediatric review, we present our practice for defining acute pulmonary exacerbation, deciding treatment location, initiating treatment either in-person or remotely, determining the frequency of airway clearance, selecting antimicrobial therapy, recommending timing for follow-up visit, and recognizing and managing treatment failures.

PMID: 27429564 [PubMed]

Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation.

Am J Respir Crit Care Med. 2016 Mar 1;193(5):552-60

Authors: Kraft BD, Suliman HB, Colman EC, Mahmood K, Hartwig MG, Piantadosi CA, Shofer SL

Abstract
RATIONALE: Central airway stenosis (CAS) after lung transplantation has been attributed in part to chronic airway ischemia; however, little is known about the time course or significance of large airway hypoxia early after transplantation.
OBJECTIVES: To evaluate large airway oxygenation and hypoxic gene expression during the first month after lung transplantation and their relation to airway complications.
METHODS: Subjects who underwent lung transplantation underwent endobronchial tissue oximetry of native and donor bronchi at 0, 3, and 30 days after transplantation (n = 11) and/or endobronchial biopsies (n = 14) at 30 days for real-time polymerase chain reaction of hypoxia-inducible genes. Patients were monitored for 6 months for the development of transplant-related complications.
MEASUREMENTS AND MAIN RESULTS: Compared with native endobronchial tissues, donor tissue oxygen saturations (Sto2) were reduced in the upper lobes (74.1 ± 1.8% vs. 68.8 ± 1.7%; P < 0.05) and lower lobes (75.6 ± 1.6% vs. 71.5 ± 1.8%; P = 0.065) at 30 days post-transplantation. Donor upper lobe and subcarina Sto2 levels were also lower than the main carina (difference of -3.9 ± 1.5 and -4.8 ± 2.1, respectively; P < 0.05) at 30 days. Up-regulation of hypoxia-inducible genes VEGFA, FLT1, VEGFC, HMOX1, and TIE2 was significant in donor airways relative to native airways (all P < 0.05). VEGFA, KDR, and HMOX1 were associated with prolonged respiratory failure, prolonged hospitalization, extensive airway necrosis, and CAS (P < 0.05).
CONCLUSIONS: These findings implicate donor bronchial hypoxia as a driving factor for post-transplantation airway complications. Strategies to improve airway oxygenation, such as bronchial artery re-anastomosis and hyperbaric oxygen therapy merit clinical investigation.

PMID: 26488115 [PubMed - indexed for MEDLINE]

Machine learning classification of surgical pathology reports and chunk recognition for information extraction noise reduction.

Artif Intell Med. 2016 Jun;70:77-83

Authors: Napolitano G, Marshall A, Hamilton P, Gavin AT

Abstract
BACKGROUND AND AIMS: Machine learning techniques for the text mining of cancer-related clinical documents have not been sufficiently explored. Here some techniques are presented for the pre-processing of free-text breast cancer pathology reports, with the aim of facilitating the extraction of information relevant to cancer staging.
MATERIALS AND METHODS: The first technique was implemented using the freely available software RapidMiner to classify the reports according to their general layout: 'semi-structured' and 'unstructured'. The second technique was developed using the open source language engineering framework GATE and aimed at the prediction of chunks of the report text containing information pertaining to the cancer morphology, the tumour size, its hormone receptor status and the number of positive nodes. The classifiers were trained and tested respectively on sets of 635 and 163 manually classified or annotated reports, from the Northern Ireland Cancer Registry.
RESULTS: The best result of 99.4% accuracy - which included only one semi-structured report predicted as unstructured - was produced by the layout classifier with the k nearest algorithm, using the binary term occurrence word vector type with stopword filter and pruning. For chunk recognition, the best results were found using the PAUM algorithm with the same parameters for all cases, except for the prediction of chunks containing cancer morphology. For semi-structured reports the performance ranged from 0.97 to 0.94 and from 0.92 to 0.83 in precision and recall, while for unstructured reports performance ranged from 0.91 to 0.64 and from 0.68 to 0.41 in precision and recall. Poor results were found when the classifier was trained on semi-structured reports but tested on unstructured.
CONCLUSIONS: These results show that it is possible and beneficial to predict the layout of reports and that the accuracy of prediction of which segments of a report may contain certain information is sensitive to the report layout and the type of information sought.

PMID: 27431038 [PubMed - in process]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/07/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/07/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers.

Cancers (Basel). 2016;8(7)

Authors: Ahmed K, Shaw HV, Koval A, Katanaev VL

Abstract
Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed drugs currently exist, and only very few candidates have reached early phase clinical trials. Among different strategies to develop WNT-targeting anti-cancer therapies, repositioning of existing drugs previously approved for other diseases is a promising approach. Nonsteroidal anti-inflammatory drugs like aspirin, the anti-leprotic clofazimine, and the anti-trypanosomal suramin are among examples of drugs having recently revealed WNT-targeting activities. In total, 16 human-use drug compounds have been found to be working through the WNT pathway and show promise for their prospective repositioning against various cancers. Advances, hurdles, and prospects of developing these molecules as potential drugs against WNT-dependent cancers, as well as approaches for discovering new ones for repositioning, are the foci of the current review.

PMID: 27429001 [PubMed - as supplied by publisher]

mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice.

FASEB J. 2016 Mar;30(3):1263-75

Authors: Sampson LL, Davis AK, Grogg MW, Zheng Y

Abstract
Intestinal stem cells (ISCs) drive small intestinal epithelial homeostasis and regeneration. Mechanistic target of rapamycin (mTOR) regulates stem and progenitor cell metabolism and is frequently dysregulated in human disease, but its physiologic functions in the mammalian small intestinal epithelium remain poorly defined. We disrupted the genes mTOR, Rptor, Rictor, or both Rptor and Rictor in mouse ISCs, progenitors, and differentiated intestinal epithelial cells (IECs) using Villin-Cre. Mutant tissues and wild-type or heterozygous littermate controls were analyzed by histologic immunostaining, immunoblots, and proliferation assays. A total of 10 Gy irradiation was used to injure the intestinal epithelium and induce subsequent crypt regeneration. We report that mTOR supports absorptive enterocytes and secretory Paneth and goblet cell function while negatively regulating chromogranin A-positive enteroendocrine cell number. Through additional Rptor, Rictor, and Rptor/Rictor mutant mouse models, we identify mechanistic target of rapamycin complex 1 as the major IEC regulatory pathway, but mechanistic target of rapamycin complex 2 also contributes to ileal villus maintenance and goblet cell size. Homeostatic adult small intestinal crypt cell proliferation, survival, and canonical wingless-int (WNT) activity are not mTOR dependent, but Olfm4(+) ISC/progenitor population maintenance and crypt regeneration postinjury require mTOR. Overall, we conclude that mTOR regulates multiple IEC lineages and promotes stem and progenitor cell activity during intestinal epithelium repair postinjury.

PMID: 26631481 [PubMed - indexed for MEDLINE]