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IPA is an all-in-one, web-based software application that enables analysis, integration, and understanding of data from gene expression, miRNA, and SNP microarrays, as well as metabolomics, proteomics, and RNAseq experiments. IPA can also be used for analysis of small-scale experiments that generate gene and chemical lists. IPA allows searches for targeted information on genes, proteins, chemicals, and drugs, and building of interactive models of experimental systems. Data analysis and search capabilities help in understanding the significance of data, specific targets, or candidate biomarkers in the context of larger biological or chemical systems. The software is backed by the Ingenuity Knowledge Base of highly structured, detail-rich biological and chemical findings. Learn more about QIAGEN Ingenuity Pathway Analysis (IPA).
Comparison Analysis provides quick visualization of canonical pathway score trends across dose, time, or other factors using the Comparison Analysis heat map. Prioritize by score, hierarchical cluster, or trend.>
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Changes in the phosphorylation states of proteins provide an important regulatory mechanism in mammalian cells. Discover upstream regulators and causal network master regulators that may be driving the changes in phosphorylation levels of the proteins in your phosphoproteomics dataset. Visualize how the phosphorylated proteins affect Canonical Signaling pathways. These results provide testable hypotheses by identifying potential signaling cascades from the phosphorylation patterns in your dataset.>
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Path Designer transforms networks and pathways into publication-quality pathway graphics rich with color, customized text and fonts, biological icons, organelles, and custom backgrounds. Expand and explore pathways using the high-quality content stored in Ingenuity IPA.
QIAGEN Ingenuity Pathway Analysis (IPA) allows users to comprehensively analyze gene expression data and infer the underlying causes of the observed fold changes, predict downstream effects and discover new targets or candidate biomarkers. Users can interactively browse and visualize significant pathways, upstream regulators, interaction networks and related studies using IPA's extensive Knowledge Base. To access the software, please follow these steps:
Ingenuity Pathway Analysis (IPA) helps researchers to quickly visualize and understand complex 'omics data and perform insightful data analysis and interpretation by placing experimental results within the context of biological systems.
Nerve injury is a common and difficult clinical problem worldwide with a high disability rate. Different from the central nervous system, the peripheral nervous system is able to regenerate after injury. Wallerian degeneration in the distal nerve stump contributes to the construction of a permissible microenvironment for peripheral nerve regeneration. To gain new molecular insights into Wallerian degeneration, this study aimed to identify differentially expressed genes and elucidate significantly involved pathways and cellular functions in the distal nerve stump following nerve injury. Microarray analysis showed that a few genes were differentially expressed at 0.5 and 1 h post nerve injury and later on a relatively larger number of genes were up-regulated or down-regulated. Ingenuity pathway analysis indicated that inflammation and immune response, cytokine signaling, cellular growth and movement, as well as tissue development and function were significantly activated following sciatic nerve injury. Notably, a cellular function highly related to nerve regeneration, which is called Nervous System Development and Function, was continuously activated from 4 days until 4 weeks post injury. Our results may provide further understanding of Wallerian degeneration from a genetic perspective, thus aiding the development of potential therapies for peripheral nerve injury.
Figure 6. qPCR analysis of genes involved in Nervous System Development and Function following sciatic nerve transection. The relative expression levels of (A) MMP9, (B) BDNF, (C) MAG, (D) MAL, (E) SHH, (F) SLC6A17, and (G) RET were calculated using comparative Ct with GAPDH as the reference gene. Data are summarized from 3 independent experiments and values are shown as the means SEM. The asterisk indicates significant difference: *p-value < 0.05; **p-value < 0.01; ***p-value < 0.001 as compared to contrsol (0 h post injury).
The Wallerian degeneration process, since its first observation by Augustus Volney Waller in 1850, has been widely studied. Over the last 160 years, however, most studies on Wallerian degeneration have been limited to morphological descriptions while molecular changes during Wallerian degeneration have not been fully elucidated (Lee and Wolfe, 2000; Zochodne, 2000; Geuna et al., 2009; Sta et al., 2014). With the development of high-throughput genomic tools, such as microarray analysis and deep sequencing, it is now possible and preferable to detect the gene expression changes during Wallerian degeneration in order to identify the molecular basis of the morphological changes.
Microarray technique provides an easy way to screen many thousands of genes or proteins in one assay, and is widely used to detect expression change patterns under various physiological and pathological conditions. In a few previous studies in our group, microarray was used to investigate the expression profiles in the distal nerve stump following peripheral nerve injury, and a number of up-regulated or down-regulated molecules were identified during Wallerian degeneration (Yao et al., 2012, 2013; Li M. et al., 2013; Li et al., 2014). Furthermore, many statistical and bioinformatic tools, including Hierarchical clustering, Euclidean distance matrix, Venny plot analysis, Volcano plot analysis, principal component analysis, Gene Ontology analysis, and Kyoto Enrichment of Genes and Genomes pathway analysis, have been applied to determine key molecules, signaling pathways, and biological processes during Wallerian degeneration. For example, Gene Ontology analysis suggested that differentially expressed genes in the distal nerve stump could be mainly divided into functional groups with regulatory functions, including cell communication, cell transport, and transcriptional regulation (Bosse et al., 2006). Biological processes, such as response to stimulus, inflammatory response, immune response, cell proliferation, migration, and apoptosis, axon guidance, myelination, signal transduction, and protein kinase activity, were also investigated (Jiang et al., 2014). Despite these findings, it is still required to further investigate the molecular changes of Wallerian degeneration from a genetic perspective.
Immediately after peripheral nerve injury, the most significant pathways and cellular functions were found to be inflammatory and immune response, which remained to be activated until 4 weeks post nerve injury. Meanwhile, immune signal molecules and cytokines were also activated rapidly after injury. Inflammation reaction and immune response are protective reactions against injury stimuli (Donnelly and Popovich, 2008; Benowitz and Popovich, 2011; Dubový et al., 2013; Li S. et al., 2013). Timely inflammatory and immune reactions are highly relevant with Wallerian degeneration, and benefit subsequent nerve repair and functional recovery (Dubový, 2011; Gaudet et al., 2011). Morphological observation of Wallerian degeneration suggests that macrophages migrate to the injured site in an early stage post injury (Geuna et al., 2009). Our study, from the genetic aspect, confirmed the critical roles of macrophages during Wallerian degeneration. Moreover, our finding that inflammation and immune response was continuously activated is consistent with previous observation in a model of sciatic nerve crush injury (Yi et al., 2015).
At relatively later time points post peripheral nerve injury, the most significant canonical pathways and cellular functions were found to be tissue development and function. The IPA-derived gene network suggested that the category of Nervous System Development and Function was highly scored from 6 h to 4 weeks post nerve injury. The examination for the genes involved in Nervous System Development and Function indicated that MMP9 and BDNF were significantly up-regulated starting from 6 h post nerve injury. MMP9, a gelatinase, belongs to the MMP zinc-containing endopeptidase family. During tissue remodeling, MMPs mediate the breakdown of the extracellular matrix (ECM), a key network containing physical and biochemical cues for tissue regeneration (Ravanti and Kähäri, 2000; Dubový, 2004; Chen et al., 2007). Previous studies also revealed that the MMP9 expression was often elevated following nerve injury. However, the up-regulation of MMP9 was largely compromised in mice with delayed Wallerian degeneration (Shubayev et al., 2006; Barrette et al., 2010). Up-regulated MMP9 stimulates the recruitment and migration of macrophages, mediates the differentiation of myelinating Schwann cells, and thus benefits nerve regeneration (Shubayev et al., 2006; Kim et al., 2012). Our earlier studies also demonstrated that two other members of the MMP family, MMP7 and MMP12, were kept up-regulated following nerve injury (Jiang et al., 2014; Qin et al., 2016). All these results highlight the central roles of the MMP family in nerve regeneration. BDNF is a well-known neurotrophic factor that promotes neuronal survival and activity and stimulates axon growth (Braun et al., 1996; Lykissas et al., 2007). We have previously reported on the up-regulation of the mRNA expression of BDNF at 1, 4, 7, and 14 days post nerve crush injury (Yi et al., 2016). It has been known that after peripheral nerve injury, Schwann cells not only proliferate to form the bands of Bungner, but also produce a range of neurotrophic factors, including BDNF (Frostick et al., 1998; Faroni et al., 2013; Jang et al., 2016). Therefore, the up-regulated BDNF in the distal nerve stump would augment axonal regrowth and promote nerve regeneration. In this study, besides MMP9 and BDNF, myelin-related genes (MAG and MAL) were also found to be up-regulated starting from 4 days post injury. Myelin is an important inhibiting factor for neurite growth and nerve repair (Bähr and Przyrembel, 1995; David et al., 1995). Why were not the myelin-related genes up-regulated until a relatively later stage post injury? It may be because that at an early stage after nerve injury only non-myelinating Schwann cells, but not myelinating Schwann cells, enter into the cell cycle to avoid negative factors for nerve regeneration (Murinson et al., 2005), but later on myelinating Schwann cells start to proliferate and to form myelin sheaths (Liu et al., 1995; Vargas and Barres, 2007). Accordingly, the expression change of myelin-related genes might reflect that Schwann cells play different roles at different time periods during Wallerian degeneration.
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