P2RX7 genotype association in severe sepsis identified by a novel Multi-Individual Array for rapid screening and replication of risk SNPs

Geistlinger, J.; Du, Wei‐Dong; Groll, Jürgen; Liu, F.; Hoegel, Josef; Foehr, K.J.; Pasquarelli, A.; Schneider, Eduarda Maria

doi:10.1016/j.cca.2011.05.023

Cited by 20 publications

(22 citation statements)

References 34 publications

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“…The results reveal a complex sepsis-induced cerebral inflammatory cascade leading to neurovascular damage that is initiated by endothelial P2RX 7 signaling ( Figure 9G ). Recently, an activating single-nucleotide polymorphism in P2RX 7 was shown to increase the risk of death in patients with severe sepsis 52 . Presently, only supportive therapy is available for the treatment of SE, which is associated with high mortality 53 , 54 , 55 .…”

Section: Discussionmentioning

confidence: 99%

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

et al. 2015

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Septic encephalopathy (SE) is a critical factor determining sepsis mortality. Vascular inflammation is known to be involved in SE, but the molecular events that lead to the development of encephalopathy remain unclear. Using time-lapse in vivo two-photon laser scanning microscopy, we provide the first direct evidence that cecal ligation and puncture in septic mice induces microglial trafficking to sites adjacent to leukocyte adhesion on inflamed cerebral microvessels. Our data further demonstrate that septic injury increased the chemokine CXCL1 level in brain endothelial cells by activating endothelial P2RX7 and eventually enhanced the binding of Mac-1 (CD11b/CD18)-expressing leukocytes to endothelial ICAM-1. In turn, leukocyte adhesion upregulated endothelial CX3CL1, thereby triggering microglia trafficking to the injured site. The sepsis-induced increase in endothelial CX3CL1 was abolished in CD18 hypomorphic mutant mice. Inhibition of the P2RX7 pathway not only decreased endothelial ICAM-1 expression and leukocyte adhesion but also prevented microglia overactivation, reduced brain injury, and consequently doubled the early survival of septic mice. These results demonstrate the role of the P2RX7 pathway in linking neurovascular inflammation to brain damage in vivo and provide a rationale for targeting endothelial P2RX7 for neurovascular protection during SE.

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Section: Discussionmentioning

confidence: 99%

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

et al. 2015

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“…A number of studies of SNPs in the P2RX7 gene have been carried out over a period of more than a decade in order to examine a potential role of the human P2X7 receptor in the aetiology of a variety of clinical conditions, including chronic lymphocytic leukaemia (CCL) [46,47,48,49,50,51], affective mood disorders [52,53,54,55], multiple sclerosis [56], chronic pain [14], systemic lupus erythematosus, rheumatoid arthritis [57,58,59], childhood febrile seizure [60], ischemic stroke, ischemic heart disease [61], tuberculosis [62,63,64,65,66], sepsis [67], toxoplasmosis [68,69], osteoporosis, and bone fracture [70,71,72,73,74]. Table 1 provides a brief summary of the NS-SNPs that have been associated with or implicated in altering susceptibility to particular disease condition(s).…”

Section: Non-synonymous Single Nucleotide Polymorphisms (Ns-snps) mentioning

confidence: 99%

“…One recent study employing the multi-individual array platform, capable of simultaneously identifying variations in the same nucleotide in thousands of samples, screened DNA from blood samples taken from 95 patients with severe sepsis and 518 control subjects [67]. This study found that the prevalence of two NS-SNPs, 489C>T and 1405A>G for the H155Y and Q460R mutations respectively, were significantly higher in patients suffering from severe sepsis following surgical trauma, implying the presence of these NS-SNPs as a potential risk factor for sepsis.…”

Section: Non-synonymous Single Nucleotide Polymorphisms (Ns-snps) mentioning

confidence: 99%

Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers

Caseley

Muench

Roger

et al. 2014

IJMS

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P2X receptors are Ca2+-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are widespread in the P2RX genes encoding the human P2X receptors, particularly the human P2X7 receptor. This article will provide an overview of the non-synonymous SNPs (NS-SNPs) that have been associated with or implicated in altering the susceptibility to pathologies or disease conditions, and discuss the consequences of the mutations resulting from such NS-SNPs on the receptor functions. Disease-associated NS-SNPs in the P2RX genes have been valuable in understanding the disease etiology and the receptor function, and are promising as biomarkers to be used for the diagnosis and development of stratified therapeutics.

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“…This can be achieved by simple layer incubation or by patterning techniques without the need for additional cross-linkers. Higher reactivity of thiols and amines can also be used for preferential binding, and the system may be used for microarray applications and on chip single base extension for single-nucleotide polymorphism detection [1]. For the latter, another advantage of the system becomes apparent.…”

Section: Introductionmentioning

confidence: 99%

“…Surfaces used in biosensors and for biomolecular interaction studies need to fulfill two major criteria; minimization of unspecific interactions and high specificity for the recognition of immobilized bioactive ligands [1,2]. The combination of these two properties ensures control of the interaction of biomolecules on the surface with high signal-to-noise ratio for the specific biomolecular detection system.…”

Section: Introductionmentioning

confidence: 99%

A hydrogel-based versatile screening platform for specific biomolecular recognition in a well plate format

et al. 2012

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Precise determination of biomolecular interactions in high throughput crucially depends on a surface coating technique that allows immobilization of a variety of interaction partners in a non-interacting environment. We present a one-step hydrogel coating system based on isocyanate functional six-arm poly(ethylene oxide)-based star polymers for commercially available 96-well microtiter plates that combines a straightforward and robust coating application with versatile bio-functionalization. This system generates resistance to unspecific protein adsorption and cell adhesion, as demonstrated with fluorescently labeled bovine serum albumin and primary human dermal fibroblasts (HDF), and high specificity for the assessment of biomolecular recognition processes when ligands are immobilized on this surface. One particular advantage is the wide range of biomolecules that can be immobilized and convert the per se inert coating into a specifically interacting surface. We here demonstrate the immobilization and quantification of a broad range of biochemically important ligands, such as peptide sequences GRGDS and GRGDSK-biotin, the broadly applicable coupler molecule biocytin, the protein fibronectin, and the carbohydrates N-acetylglucosamine and N-acetyllactosamine. A simplified protocol for an enzyme-linked immunosorbent assay was established for the detection and quantification of ligands on the coating surface. Cell adhesion on the peptide and protein-modified surfaces was assessed using HDF. All coatings were applied using a one-step preparation technique, including bioactivation, which makes the system suitable for high-throughput screening in a format that is compatible with the most routinely used testing systems.

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P2RX7 genotype association in severe sepsis identified by a novel Multi-Individual Array for rapid screening and replication of risk SNPs

Cited by 20 publications

References 34 publications

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

P2RX7 sensitizes Mac-1/ICAM-1-dependent leukocyte-endothelial adhesion and promotes neurovascular injury during septic encephalopathy

Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers

A hydrogel-based versatile screening platform for specific biomolecular recognition in a well plate format

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