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A network-based analysis of systemic inflammation in humans

ABSTRACT: Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans. Keywords: Gene expression profiling of human blood leukocytes in response to in vivo endotoxin administration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE3284 | GEO | 2005/09/14

SECONDARY ACCESSION(S): PRJNA92945

REPOSITORIES: GEO

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Project description:Sub-thalamic deep brain stimulation (DBS) reversibly modulates ParkinsonM-bM-^@M-^Ys disease (PD) motor symptoms, providing an unusual opportunity to compare leukocyte transcripts in the same subjects before and after neurosurgery and after disconnecting the stimulus (ON-and OFF-stimulus). Here, we report rapid stimulus-induced and largely reversible changes in PD leukocyte transcripts, which were larger in scope than the disease-induced changes. These transcript changes classified advanced pre- from post-surgery PD patients and discriminated patients from controls. Moreover, the extent of changes correlated with the neurological efficacy of the DBS neurosurgery, and covered both regulatory pathways and individual transcript changes, e.g. SNCA, PARK7 and the splicing factor SFRS1. Following 1 hour OFF-stimulus, these changes were largely reversed. We extracted from these differences a modified transcripts signature which discriminated controls from advanced PD patients, pre- from post-surgery and ON-from OFF-stimulus conditions. A further gene-list independent analysis detected reversed pathways. Our findings suggest future uses of this approach and the discovered molecular signature for early diagnostics of PD and for identifying novel targets for therapeutic intervention in this and other DBS-treatable neurological diseases. 27 Total samples were analyzed. Study design included four conditions. PD patients (n=7) leukocyte blood samples were examined at 3 time points, and healthy control subjects (n=6) were examined once each. Samples were taken 1 day prior to sub-thalamic nucleous (STN) DBS treatment, several months after STN-DBS treatment upon optimal stimulation and following one hour electrical stimulation cessation. The off stimulation caused recruitment of the disease symptoms as measured by the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). The different stages are designated: S1 (pre-treatment), S2 (post STN-DBS) and S3 (upon off stimulation). All patients were on dopamine replacement therapy (DRT) when examined pre- and post-DBS off stimulation (albeit with reduced therapy dose post-DBS). To reduce biological variability among the samples which is not related to the study, only male subjects were included in this study. Samples from six age- and gender- matched healthy control subjects served to detect disease modified transcripts and for pre- and post- treatment comparisons. The study was approved by the human review board at the Hadassah University Hospital, Ein-Kerem (no. 6-07.09.07) in accordance with the Declaration of Helsinki. All study participants signed informed consent.

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A network-based analysis of systemic inflammation in humans

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