Aberrant Niche Signaling in the Etiopathogenesis of Ulcerative Colitis

Kini, Archana; Thangaraj, Kavitha R.; Simon, Ebby George; Shivappagowdar, Abhishek; Thiagarajan, Divya; Abbas, Salar; Ramachandran, Anup; Venkatraman, Aparna

doi:10.1097/mib.0000000000000523

Cited by 10 publications

(17 citation statements)

References 61 publications

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“…It is also well known that combination of disease-associated variants of ATG16L1 and NOD2/CARD15 leads to synergistically increased susceptibility for CD, indicating a possible crosstalk between NOD2- and ATG16L1-mediated processes in the pathogenesis of CD [34]. Notably Kini et al [35] indicated that changes in signaling through Wnt primarily affected colonic stem cells, whereas Notch affected progenitor function, providing new insights into the development of inflammation and relapse in UC. As depicted in our results, the central role of all these pathways is highlighted.…”

Section: Discussionmentioning

confidence: 99%

Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach

et al. 2019

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Background: Crohn's disease (CD) and Ulcerative colitis (UC) are the two main entities of inflammatory bowel disease (IBD). Previous works have identified more than 200 risk factors (including loci and signaling pathways) in populations of predominantly European ancestry. Our study was conducted on an extended population-specific cohort of 573 Greek IBD patients (364 CD and 209 UC) and 445 controls. Aims: To highlight the different genetic and functional background of IBD and its phenotypes, utilizing contemporary systems bioinformatics methodologies. Methods: Disease-associated SNPs, obtained via our own 89 loci IBD risk GWAS panel, were detected with the whole genome association analysis toolset PLINK. These SNPs were used as input for 2 novel and different pathway analysis methods to detect functional interactions. Specifically, PathwayConnector was used to create complementary networks of interacting pathways whereas; the online database of protein interactions STRING provided protein-protein association networks and their derived pathways. Network analyses metrics were employed to identify proteins with high significance and subsequently to rank the signaling pathways those participate in. Results: The reported complementary pathway and enriched protein-protein association networks reveal several novel and well-known key players, in the functional background of IBD like Toll-like receptor, TNF, Jak-STAT, PI3K-Akt, T cell receptor, Apoptosis, MAPK and B cell receptor signaling pathways. IBD subphenotypes are found to have distinct genetic and functional profiles which can contribute to their accurate identification and classification. As a secondary result we identify an extended network of diseases with common molecular background to IBD. Conclusions: IBD's burden on the quality of life of patients and intricate functional background presents us constantly with new challenges. Our data and methodology provide researchers with new insights to a specific population, but also, to possible differentiation markers of disease classification and progression. This work, not only provides new insights into the interplay among IBD risk variants and their related signaling pathways, elucidates the mechanisms underlying IBD and its clinical sequelae, but also, introduces a generalized bioinformatics-based methodology which can be applied to studies of different disorders.

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Section: Discussionmentioning

confidence: 99%

Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach

et al. 2019

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“…In closing, while cellular descriptions and molecular signals that control cell proliferation and cell mutations during carcinogenesis in UC have received much attention ( [35][36][37][38][39][40], the signals that might be instrumental in designing morphogenesis (41) resulting in the "etching" of various CCC phenotypes in UC, have remained unattended.…”

Section: Discussionmentioning

confidence: 99%

Morphological Classification of Corrupted Colonic Crypts in Ulcerative Colitis

Rubio

Schmidt

2018

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“…In addition, aberrant niche signaling was observed in human IBD patients (Kini et al, 2015), in line with the Paneth cell abnormalities observed in hypomorphic Atg16l1 mutant mice and in human patients carrying the ATG16L1 risk allele (Cadwell et al, 2008).…”

Section: Discussionmentioning

confidence: 57%

Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

et al. 2017

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Genetic variations of Atg16l1, Slit2 and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship between these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine (pre-EE) cells accumulate that fail to differentiate into properly functioning secretory EE cells. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE cell generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling triggers an intestinal inflammatory response. Surprisingly, analysis of Rab19 and domainspecific Atg16 mutants indicates that their stem cell niche regulatory function is independent of autophagy. Our study reveals how mutations in these different genes may contribute to IBD.

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Aberrant Niche Signaling in the Etiopathogenesis of Ulcerative Colitis

Abstract: Our results thus provide new insights into the development of inflammation and relapse in UC and suggest that the stem cell niche in the colon may influence pathogenesis of the disease.

Cited by 10 publications

References 61 publications

Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach

Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach

Morphological Classification of Corrupted Colonic Crypts in Ulcerative Colitis

Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

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