Inflammatory Bowel Disease and Endothelin-1

Angerio, Allan D.; Bufalino, Dominick; Bresnick, Melissa; Bell, C.R.W.; Brill, Sarah

doi:10.1097/00002727-200504000-00013

Cited by 9 publications

(10 citation statements)

References 47 publications

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“…Endothelin-1 Receptor (EDNRA): Enhances inflammation through recruitment of T lymphocytes and neutrophils, and release of pro-inflammatory and profibrotic cytokines [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

“…Excessive production of endothelin-1 in the GI tract due to immune system activation causes dysregulation of cytokine production. Endothelin-1, produced by endothelial cells, is important in inflammation where they recruit circulating leukocytes to the endothelium [ 18 ]. Overproduction of Endothelin-1 is thus associated with excessive inflammation that characterizes IBD.…”

Section: Discussionmentioning

confidence: 99%

“…Excessive degranulation of mast cells causes damage to intestinal mucosa. Studies have shown an increased presence of endothelin-1 in tissues from patients with IBD [ 18 ]. It has been suggested that vasoconstriction induced by the molecule makes it act as a chemoattractant which exacerbates tissue damage in IBD due to inappropriate inflammation [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown an increased presence of endothelin-1 in tissues from patients with IBD [ 18 ]. It has been suggested that vasoconstriction induced by the molecule makes it act as a chemoattractant which exacerbates tissue damage in IBD due to inappropriate inflammation [ 18 ]. Thus, reducing endothelin-1 activity through blocking endothelin-1 receptors appears to be a potential strategy in IBD drug development.…”

Section: Discussionmentioning

confidence: 99%

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Computational drug repurposing for inflammatory bowel disease using genetic information

Grenier

2019

Computational and Structural Biotechnology Journal

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As knowledge of the genetics behind inflammatory bowel disease (IBD) has continually improved, there has been a demand for methods that can use this data in a clinically significant way. Genome-wide association analyses for IBD have identified 232 risk genetic loci for the disorder. While identification of these risk loci enriches our understanding of the underlying biology of the disorder, their identification does not serve a clinical purpose. A potential use of this genetic information is to look for potential IBD drugs that target these loci in a procedure known as drug repurposing. The demand for new drug treatments for IBD is high due to the side effects and high costs of current treatments. We hypothesize that IBD genetic variants obtained from GWAS and the candidate genes prioritized from the variants have a causal relationship with IBD drug targets. A computational drug repositioning study was done due to its efficiency and inexpensiveness compared to traditional in vitro or biochemical approaches. Our approach for drug repurposing was multi-layered; it not only focused on the interactions between drugs and risk IBD genes, but also the interactions between drugs and all of the biological pathways the risk genes are involved in. We prioritized IBD candidate genes using identified genetic variants and identified potential drug targets and drugs that can be potentially repositioned or developed for IBD using the identified candidate genes. Our analysis strategy can be applied to repurpose drugs for other complex diseases using their risk genes identified from genetic analysis.

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“…Endothelin-1 Receptor (EDNRA): Enhances inflammation through recruitment of T lymphocytes and neutrophils, and release of pro-inflammatory and profibrotic cytokines [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Computational drug repurposing for inflammatory bowel disease using genetic information

Grenier

2019

Computational and Structural Biotechnology Journal

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“…Numerous roles for EDN1 in vascular diseases of the liver, lungs and kidneys have been described, including chronic obstructive pulmonary disease (COPD) (Dorrington, 1999; Polikepahad et al, 2006), chronic kidney disease (Dhaun et al, 2012; Gagliardini et al, 2011), hypertension (Moorhouse et al, 2013; Speed and Pollock, 2013) and cirrhosis (Moore, 2004). Elevated EDN1 levels have also been implicated in diseases that include Alzheimer’s disease (Palmer et al, 2013), Sickle cell anemia (Morris, 2008), inflammatory bowel disease (Angerio et al, 2005), demylinating diseases (Hammond et al, 2014; Haufschild et al, 2001) and infectious diseases (Freeman et al, 2014). In addition, EDN1 is also implicated in multiple aspects of cancer progression, including epithelial to mesenchymal transition (EMT) (Bagnato and Rosano, 2007) and in stimulating tumor angiogenesis (Knowles et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cre recombinase-regulated Endothelin1 transgenic mouse lines: Novel tools for analysis of embryonic and adult disorders

Tavares

Clouthier

2015

Developmental Biology

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Endothelin-1 (EDN1) influences both craniofacial and cardiovascular development and a number of adult physiological conditions by binding to one or both of the known endothelin receptors, thus initiating multiple signaling cascades. Animal models containing both conventional and conditional loss of the Edn1 gene have been used to dissect EDN1 function in both embryos and adults. However, while transgenic Edn1 over-expression or targeted genomic insertion of Edn1 has been performed to understand how elevated levels of Edn1 result in or exacerbate disease states, an animal model in which Edn1 over-expression can be achieved in a spatiotemporal-specific manner has not been reported. Here we describe the creation of Edn1 conditional over-expression transgenic mouse lines in which the chicken β-actin promoter and an Edn1 cDNA are separated by a strong stop sequence flanked by loxP sites. In the presence of Cre, the stop cassette is removed, leading to Edn1 expression. Using the Wnt1-Cre strain, in which Cre expression is targeted to the Wnt1-expressing domain of the central nervous system (CNS) from which neural crest cells (NCCs) arise, we show that stable CBA-Edn1 transgenic lines with varying EDN1 protein levels develop defects in NCC-derived tissues of the face, though the severity differs between lines. We also show that Edn1 expression can be achieved in other embryonic tissues utilizing other Cre strains, with this expression also resulting in developmental defects. CBA-Edn1 transgenic mice will be useful in investigating diverse aspects of EDN1-mediated-development and disease, including understanding how NCCs achieve and maintain a positional and functional identity and how aberrant EDN1 levels can lead to multiple physiological changes and diseases.

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Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA)

Lafzi,

Borrelli,

Baghai Sain

et al. 2024

Mol Syst Biol

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Sequencing-based spatial transcriptomics (ST) methods allow unbiased capturing of RNA molecules at barcoded spots, charting the distribution and localization of cell types and transcripts across a tissue. While the coarse resolution of these techniques is considered a disadvantage, we argue that the inherent proximity of transcriptomes captured on spots can be leveraged to reconstruct cellular networks. To this end, we developed ISCHIA (Identifying Spatial Co-occurrence in Healthy and InflAmed tissues), a computational framework to analyze the spatial co-occurrence of cell types and transcript species within spots. Co-occurrence analysis is complementary to differential gene expression, as it does not depend on the abundance of a given cell type or on the transcript expression levels, but rather on their spatial association in the tissue. We applied ISCHIA to analyze co-occurrence of cell types, ligands and receptors in a Visium dataset of human ulcerative colitis patients, and validated our findings at single-cell resolution on matched hybridization-based data. We uncover inflammation-induced cellular networks involving M cell and fibroblasts, as well as ligand-receptor interactions enriched in the inflamed human colon, and their associated gene signatures. Our results highlight the hypothesis-generating power and broad applicability of co-occurrence analysis on spatial transcriptomics data.

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Inflammatory Bowel Disease and Endothelin-1

Cited by 9 publications

References 47 publications

Computational drug repurposing for inflammatory bowel disease using genetic information

Computational drug repurposing for inflammatory bowel disease using genetic information

Cre recombinase-regulated Endothelin1 transgenic mouse lines: Novel tools for analysis of embryonic and adult disorders

Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA)

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