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Molecules 2019, 24(5), 994; https://doi.org/10.3390/molecules24050994

秒速几种赛车玩法: Differential Proteomics Reveals miR-155 as a Novel Indicator of Liver and Spleen Pathology in the Symptomatic Niemann-Pick Disease, Type C1 Mouse Model

1
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA
2
Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20879, USA
3
Laboratory for Integrative Neuroscience, University of Illinois at Chicago, Chicago, IL 60607, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Zhenbin Zhang
Received: 1 February 2019 / Revised: 25 February 2019 / Accepted: 1 March 2019 / Published: 12 March 2019
(This article belongs to the Special Issue CZE/LC-MS-based Proteomics)
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Figure 1
<p>Comparative analysis of the differential proteome of the spleen and liver of 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Differential proteins from the mass spectrometry analysis of the spleen (<bold>A</bold>) and liver (<bold>B</bold>) of <italic>Npc1</italic><sup>?/?</sup> mice where analyzed for downregulated and upregulated proteins. Evaluation of the proteome of the spleen revealed that 18.6% of the measured proteome was found to be downregulated while 2.6% was upregulated. The differential proteome of the liver was evaluated and revealed that 15.8% of the measured proteome was found to be downregulated while 7.9% was upregulated. Venn diagram analysis of the downregulated (<bold>C</bold>) and upregulated (<bold>D</bold>) proteins was performed to determine common altered proteins.</p> ">
Figure 2
<p>Pathway analysis of the differential proteome of the spleen and liver of 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Differential proteins from the mass spectrometry analysis of the spleen (<bold>A</bold>) and liver (<bold>B</bold>) of <italic>Npc1</italic><sup>?/?</sup> mice were enriched for the top 15 pathways. Significance was determined using a Right-tailed Fisher’s exact test to determine probability of pathways from the Ingenuity Pathway Analysis Knowledge Base Library to those most significantly enriched.</p> ">
Figure 3
<p>Functional analysis of the differential proteome of the spleen and liver of 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Differential proteins from the mass spectrometry analysis of the spleen (<bold>A</bold>) and liver (<bold>B</bold>) of <italic>Npc1</italic><sup>?/?</sup> mice where enriched for top biological functions. Significance was determined using a Right-tailed Fisher’s exact test to determine probability of pathways from the Ingenuity Pathway Analysis Knowledge Base Library to those most significantly enriched.</p> ">
Figure 4
<p>Upstream regulator analysis of the differential proteome of the spleen from 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Predicted upstream regulator analysis from 11-week <italic>Npc1</italic><sup>?/?</sup> mice suggest that Tcl1a is a common regulator of various deferential proteins of the spleen. Assignment was based on the Ingenuity Pathway Analysis Knowledge Base Library. GPNMB = Transmembrane glycoprotein NMB, GUSB = Beta-glucuronidase, ITGAM = Integrin alpha-M, MMP9 = Matrix metalloproteinase-9, MPEG1 = Macrophage-expressed gene 1 protein, Ngp = Nucleolar GTP-binding protein 1, SNX6 = Sorting nexin = 6, C1QC = Complement C1q subcomponent subunit C, CELA2A = Chymotrypsin-like elastase family member 2A, CTSD = Cathepsin D and CTSE = Cathepsin E.</p> ">
Figure 5
<p>Western blot analysis of Akt in spleen and liver tissue of 11-week <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice. Protein lysates from the spleen and liver of 11-week <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice (N = 3 each genotype) were subject to electrophoresis and Western blotting. Data analysis revealed decreased expression of Akt in both the (<bold>A</bold>) spleen and (<bold>B</bold>) liver of <italic>Npc1</italic><sup>?/?</sup> mice. Data is reported as relative to Gapdh.</p> ">
Figure 6
<p>miR-155 analysis of spleen and liver tissue from 9-week <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice. miR-155 was selected for evaluation by quantitative real-time PCR in spleen and liver tissue from <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice (N = 5 for each genotype). The levels of miR-155 were significantly decreased in the (<bold>A</bold>) spleen and increased in the (<bold>B</bold>) liver of <italic>Npc1</italic><sup>?/?</sup> mice. The expression level of the miR-155 in each tissue was normalized to endogenous U6 snRNA.</p> ">

Abstract

Niemann-Pick disease, type C1 (NPC1) is a rare, autosomal recessive, lipid storage disorder caused by mutations in NPC1. As a result, there is accumulation of unesterified cholesterol and sphingolipids in the late endosomal/lysosomal system. Clinically, patients can present with splenomegaly and hepatomegaly. In the current study, we analyzed the differential proteome of the spleen in symptomatic Npc1−/− mice to complement previous studies focused on the differential proteome of the liver, and then evaluated biomolecules that may serve as tissue biomarkers. The proteomic analysis revealed altered pathways in NPC1 representing different functional categories including heme synthesis, cellular regulation and phosphoinositide metabolism in both tissues. Differential proteins included several activators of the ubiquitous and critical protein, Akt, a major kinase involved in multiple cellular processes. Evaluation of Akt revealed decreased expression in both the liver and spleen tissues of symptomatic Npc1−/− mice. Upstream regulation analysis also suggested that miR-155 may modulate the differences of known downstream protein targets observed in our dataset. Upon evaluation of miR-155, we observed an increased expression in the liver and decreased expression in the spleen of symptomatic Npc1−/− mice. Here, we propose that miR-155 may be a novel indicator of spleen and liver pathology in NPC1. View Full-Text
Keywords: Niemann-Pick type C1; spleen proteomics; AJS-ESI mass spectrometry; lysosomal storage disorder; miR-155 Niemann-Pick type C1; spleen proteomics; AJS-ESI mass spectrometry; lysosomal storage disorder; miR-155
Figures

秒速赛车是哪里的开奖 www.0dv0k.cn Figure 1

Figure 1
<p>Comparative analysis of the differential proteome of the spleen and liver of 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Differential proteins from the mass spectrometry analysis of the spleen (<bold>A</bold>) and liver (<bold>B</bold>) of <italic>Npc1</italic><sup>?/?</sup> mice where analyzed for downregulated and upregulated proteins. Evaluation of the proteome of the spleen revealed that 18.6% of the measured proteome was found to be downregulated while 2.6% was upregulated. The differential proteome of the liver was evaluated and revealed that 15.8% of the measured proteome was found to be downregulated while 7.9% was upregulated. Venn diagram analysis of the downregulated (<bold>C</bold>) and upregulated (<bold>D</bold>) proteins was performed to determine common altered proteins.</p> ">
Figure 2
<p>Pathway analysis of the differential proteome of the spleen and liver of 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Differential proteins from the mass spectrometry analysis of the spleen (<bold>A</bold>) and liver (<bold>B</bold>) of <italic>Npc1</italic><sup>?/?</sup> mice were enriched for the top 15 pathways. Significance was determined using a Right-tailed Fisher’s exact test to determine probability of pathways from the Ingenuity Pathway Analysis Knowledge Base Library to those most significantly enriched.</p> ">
Figure 3
<p>Functional analysis of the differential proteome of the spleen and liver of 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Differential proteins from the mass spectrometry analysis of the spleen (<bold>A</bold>) and liver (<bold>B</bold>) of <italic>Npc1</italic><sup>?/?</sup> mice where enriched for top biological functions. Significance was determined using a Right-tailed Fisher’s exact test to determine probability of pathways from the Ingenuity Pathway Analysis Knowledge Base Library to those most significantly enriched.</p> ">
Figure 4
<p>Upstream regulator analysis of the differential proteome of the spleen from 11-week <italic>Npc1</italic><sup>?/?</sup> mice. Predicted upstream regulator analysis from 11-week <italic>Npc1</italic><sup>?/?</sup> mice suggest that Tcl1a is a common regulator of various deferential proteins of the spleen. Assignment was based on the Ingenuity Pathway Analysis Knowledge Base Library. GPNMB = Transmembrane glycoprotein NMB, GUSB = Beta-glucuronidase, ITGAM = Integrin alpha-M, MMP9 = Matrix metalloproteinase-9, MPEG1 = Macrophage-expressed gene 1 protein, Ngp = Nucleolar GTP-binding protein 1, SNX6 = Sorting nexin = 6, C1QC = Complement C1q subcomponent subunit C, CELA2A = Chymotrypsin-like elastase family member 2A, CTSD = Cathepsin D and CTSE = Cathepsin E.</p> ">
Figure 5
<p>Western blot analysis of Akt in spleen and liver tissue of 11-week <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice. Protein lysates from the spleen and liver of 11-week <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice (N = 3 each genotype) were subject to electrophoresis and Western blotting. Data analysis revealed decreased expression of Akt in both the (<bold>A</bold>) spleen and (<bold>B</bold>) liver of <italic>Npc1</italic><sup>?/?</sup> mice. Data is reported as relative to Gapdh.</p> ">
Figure 6
<p>miR-155 analysis of spleen and liver tissue from 9-week <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice. miR-155 was selected for evaluation by quantitative real-time PCR in spleen and liver tissue from <italic>Npc1<sup>+/+</sup></italic> and <italic>Npc1</italic><sup>?/?</sup> mice (N = 5 for each genotype). The levels of miR-155 were significantly decreased in the (<bold>A</bold>) spleen and increased in the (<bold>B</bold>) liver of <italic>Npc1</italic><sup>?/?</sup> mice. The expression level of the miR-155 in each tissue was normalized to endogenous U6 snRNA.</p> ">
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Pergande, M.R.; Cougnoux, A.; Rathnayake, R.A.C.; Porter, F.D.; Cologna, S.M. Differential Proteomics Reveals miR-155 as a Novel Indicator of Liver and Spleen Pathology in the Symptomatic Niemann-Pick Disease, Type C1 Mouse Model. Molecules 2019, 24, 994.

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