Dataset Information

In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-?-induced apoptosis and proliferation by MAPKs.

ABSTRACT: Cellular responses to external stimuli depend on dynamic features of multipathway network signaling; thus, cell behavior is influenced in a complex manner by the environment and by intrinsic properties. Methods of multivariate systems analysis have provided an understanding of these convoluted effects, but only for relatively simplified examples in vitro. To determine whether such approaches could be successfully used in vivo, we analyzed the signaling network that determines the response of intestinal epithelial cells to tumor necrosis factor-? (TNF-?). We built data-driven, partial least-squares discriminant analysis (PLSDA) models based on signaling, apoptotic, and proliferative responses in the mouse small intestinal epithelium after systemic exposure to TNF-?. The extracellular signal-regulated kinase (ERK) signaling axis was a critical modulator of the temporal variation in apoptosis at different doses of TNF-? and of the spatial variation in proliferation in distinct intestinal regions. Inhibition of MEK, a mitogen-activated protein kinase kinase upstream of ERK, altered the signaling network and changed the temporal and spatial phenotypes consistent with model predictions. Our results demonstrate the dynamic, adaptive nature of in vivo signaling networks and identify natural, tissue-level variation in responses that can be deconvoluted only with quantitative, multivariate computational modeling. This study lays a foundation for the use of systems-based approaches to understand how dysregulation of the cellular network state underlies complex diseases.

SUBMITTER: Lau KS

PROVIDER: S-EPMC3963028 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs.

Lau Ken S KS Juchheim Alwin M AM Cavaliere Kimberly R KR Philips Sarah R SR Lauffenburger Douglas A DA Haigis Kevin M KM

Science signaling 20110322 165

Cellular responses to external stimuli depend on dynamic features of multipathway network signaling; thus, cell behavior is influenced in a complex manner by the environment and by intrinsic properties. Methods of multivariate systems analysis have provided an understanding of these convoluted effects, but only for relatively simplified examples in vitro. To determine whether such approaches could be successfully used in vivo, we analyzed the signaling network that determines the response of int ...[more]

PMID: 21427409

Similar Datasets

Project description:Objective.The goal of this work is to identify the spatio-temporal facets of state-of-the-art electroencephalography (EEG)-based continuous neurorobotics that need to be addressed, prior to deployment in practical applications at home and in the clinic.Approach.Nine healthy human subjects participated in five sessions of one-dimensional (1D) horizontal (LR), 1D vertical (UD) and two-dimensional (2D) neural tracking from EEG. Users controlled a robotic arm and virtual cursor to continuously track a Gaussian random motion target using EEG sensorimotor rhythm modulation via motor imagery (MI) commands. Continuous control quality was analyzed in the temporal and spatial domains separately.Main results.Axis-specific errors during 2D tasks were significantly larger than during 1D counterparts. Fatigue rates were larger for control tasks with higher cognitive demand (LR, left- and right-hand MI) compared to those with lower cognitive demand (UD, both hands MI and rest). Additionally robotic arm and virtual cursor control exhibited equal tracking error during all tasks. However, further spatial error analysis of 2D control revealed a significant reduction in tracking quality that was dependent on the visual interference of the physical device. In fact, robotic arm performance was significantly greater than that of virtual cursor control when the users' sightlines were not obstructed.Significance.This work emphasizes the need for practical interfaces to be designed around real-world tasks of increased complexity. Here, the dependence of control quality on cognitive task demand emphasizes the need for decoders that facilitate the translation of 1D task mastery to 2D control. When device footprint was accounted for, the introduction of a physical robotic arm improved control quality, likely due to increased user engagement. In general, this work demonstrates the need to consider both the physical footprint of devices, the complexity of training tasks, and the synergy of control strategies during the development of neurorobotic control.

Project description:MicroRNAs (miRNAs) play a critical role in many biological processes and are aberrantly expressed in human cancers. Particular miRNAs function either as tumor suppressors or oncogenes and appear to have diagnostic and prognostic significance. Although numerous miRNAs are dys-regulated in colorectal cancer (CRC) only a small fraction has been characterized functionally. Using high-throughput functional screening and miRNA profiling of clinical samples the present study aims at identifying miRNAs important for the control of cellular growth and/or apoptosis in CRC. The high-throughput functional screening was carried out in six CRC cell lines transfected with a pre-miR library including 319 synthetic human pre-miRs. Phenotypic alterations were evaluated by immunostaining of cleaved cPARP (apoptosis) or MKI67 (proliferation). Additionally, TaqMan Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosa and 46 microsatellite stable stage II CRC patients. Among the miRNAs that induced growth arrest and apoptosis in the CRC cell lines, and at same time were dys-regulated in the clinical samples, miR-375 was selected for further analysis. Independent in vitro analysis of transient and stable transfected CRC cell lines confirmed that miR-375 reduces cell viability through the induction of apoptotic death. We identified YAP1 as a direct miR-375 target in CRC and show that HELLS and NOLC1 are down-stream targets. Knock-down of YAP1 mimicked the phenotype induced by miR-375 over-expression indicating that miR-375 most likely exerts its pro-apoptotic role through YAP1 and its anti-apoptotic down-stream targets BIRC5 and BCL2L1. Finally, in vivo analysis of mouse xenograft tumors showed that miR-375 expression significantly reduced tumor growth. We conclude that the high-throughput screening successfully identified miRNAs that induce apoptosis and/or inhibit proliferation in CRC cells. Finally, combining the functional screening with profiling of CRC tissue samples we identified clinically relevant miRNAs and miRNA targets in CRC.

Dataset Information

In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-?-induced apoptosis and proliferation by MAPKs.

Publications

In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets