Id |
Subject |
Object |
Predicate |
Lexical cue |
T1 |
0-107 |
Sentence |
denotes |
Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema. |
T2 |
108-119 |
Sentence |
denotes |
BACKGROUND: |
T3 |
120-195 |
Sentence |
denotes |
Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. |
T4 |
196-386 |
Sentence |
denotes |
Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood. |
T5 |
387-398 |
Sentence |
denotes |
OBJECTIVES: |
T6 |
399-580 |
Sentence |
denotes |
We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin-equivalent (LSE) models and validate findings in skin of patients with AE. |
T7 |
581-589 |
Sentence |
denotes |
METHODS: |
T8 |
590-877 |
Sentence |
denotes |
Differentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG]) LSEs were identified by means of proteomic analysis (liquid chromatography-mass spectrometry) and Ingenuity Pathway Analysis. |
T9 |
878-1052 |
Sentence |
denotes |
Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence). |
T10 |
1053-1061 |
Sentence |
denotes |
RESULTS: |
T11 |
1062-1264 |
Sentence |
denotes |
Proteomic analysis identified 17 (P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). |
T12 |
1265-1385 |
Sentence |
denotes |
Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. |
T13 |
1386-1510 |
Sentence |
denotes |
Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. |
T14 |
1511-1675 |
Sentence |
denotes |
Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin. |
T15 |
1676-1688 |
Sentence |
denotes |
CONCLUSIONS: |
T16 |
1689-1856 |
Sentence |
denotes |
For the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. |
T17 |
1857-1945 |
Sentence |
denotes |
These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. |
T18 |
1946-2157 |
Sentence |
denotes |
We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. |
T19 |
2158-2297 |
Sentence |
denotes |
Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies. |
T1 |
0-107 |
Sentence |
denotes |
Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema. |
T2 |
108-119 |
Sentence |
denotes |
BACKGROUND: |
T3 |
120-195 |
Sentence |
denotes |
Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. |
T4 |
196-386 |
Sentence |
denotes |
Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood. |
T5 |
387-398 |
Sentence |
denotes |
OBJECTIVES: |
T6 |
399-580 |
Sentence |
denotes |
We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin-equivalent (LSE) models and validate findings in skin of patients with AE. |
T7 |
581-589 |
Sentence |
denotes |
METHODS: |
T8 |
590-877 |
Sentence |
denotes |
Differentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG]) LSEs were identified by means of proteomic analysis (liquid chromatography-mass spectrometry) and Ingenuity Pathway Analysis. |
T9 |
878-1052 |
Sentence |
denotes |
Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence). |
T10 |
1053-1061 |
Sentence |
denotes |
RESULTS: |
T11 |
1062-1264 |
Sentence |
denotes |
Proteomic analysis identified 17 (P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). |
T12 |
1265-1385 |
Sentence |
denotes |
Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. |
T13 |
1386-1510 |
Sentence |
denotes |
Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. |
T14 |
1511-1675 |
Sentence |
denotes |
Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin. |
T15 |
1676-1688 |
Sentence |
denotes |
CONCLUSIONS: |
T16 |
1689-1856 |
Sentence |
denotes |
For the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. |
T17 |
1857-1945 |
Sentence |
denotes |
These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. |
T18 |
1946-2157 |
Sentence |
denotes |
We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. |
T19 |
2158-2297 |
Sentence |
denotes |
Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies. |