A systems biology pipeline identifies new immune and disease related molecular signatures and networks in human cells during microgravity exposure

Abstract

Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions.

Proteomic analysis and bioluminescent reporter gene assays to investigate effects of simulated microgravity on Caco-2 cells

“…Since no evidence of G effects on cellular immuno and inflammation response was identified by the proteomics studies, an orthogonal approach based on reporter gene technology was also employed to explore simulated G effects on Nf-B, selected as archetypal proinflammatory signaling pathway. We report a lower basal activation of Nf-B in G conditions, a result that is consistent with a recent study in which 8000 molecular pathways from published global gene expression datasets of human cells grown in G were explored using a system biology pipeline [49]. In the aforementioned work, downregulation of Nf-B pathway through Notch1 signalling was identified as a pathway responsible for reduced immunity in G conditions.…”

“…Proteomics results provided no significant evidence of CYP27A1 or mitochondrial sterol 26‐hydroxylase alterations in μG. CYP27A1 is involved in bile acid biosynthesis and in the initial activation of vitamin D3, producing 25‐hydroxyvitamin D3, the latter being important in bone health . Due to well‐known effect of μG on bone loss we expected μG to elicit a significant alteration on CYP27A1 transcriptional activity; conversely we did not observe such an effect, thus supporting the proteomics evidence.…”

Oxidative Stress and Space Biology An Organ-Based Approach

“…Within a period of three days to a month, relatively low doses of radiation (≤2 Gy) lead to progressive loss of cancellous bone, as shown by our group and others [34,35,[141][142][143][144], which is preceeded by a rapid increase in expression levels of inflammatory cytokines such as IL1 and TNFα and pro-osteoclastogenic signals RANKL and MCP1 as well as the oxidative defense gene, NRF2 [34,35]. On the basis of these findings, we hypothesized that diets or drugs capable of preventing early increases in these molecular signals can mitigate cancellous bone loss caused by both low LET and high LET radiation.…”

Transcriptomic changes in an animal-bacterial symbiosis under modeled microgravity conditions

“…The physical factors associated with the space environment present a unique set of stresses on biological systems. Of these physical factors the reduction in gravity, or microgravity, is one of the most widely studied1234. The large-scale physiological effects of microgravity on animals are relatively well known.…”

“…The large-scale physiological effects of microgravity on animals are relatively well known. For example in humans, microgravity conditions result in bone loss, upwards to 3% per month5, permutations to both the adaptive and innate immune systems367, and a potential increased risk of bacterial and viral infections8910111213. Although the overarching phenotypes associated with microgravity exposure have been observed for decades, the underlying etiology of these effects at the cellular and biomolecular level are not yet fully delineated.…”