A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression
| العنوان: | A Functional Polymorphism-Mediated Disruption of EGR1/ADAM10 Pathway Confers the Risk of Sepsis Progression |
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| المؤلفون: | Yujie Cai, Jia Li, Tian Zhao, Yan Wang, Huiyi Chen, Wenyan Wei, Jingqi Yang, Lili Cui, Yiming Shao, Zhipeng Lai, Hui Mai, Weihao Fan, Xiaohui Li, Shoubao Tao, Feng Chen, Xiongjin Chen, Furong Lu, Furong Sun, Wenying Zhang, Mingqian Ou, Ting Zou, Pei Tang |
| المصدر: | mBio, Vol 10, Iss 4 (2019) mBio mBio, Vol 10, Iss 4, p e01663-19 (2019) |
| بيانات النشر: | American Society for Microbiology, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, Molecular Biology and Physiology, China, EGR1, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Microbiology, Proinflammatory cytokine, polymorphism, Pathogenesis, Sepsis, sepsis, 03 medical and health sciences, ADAM10 Protein, Mice, 0302 clinical medicine, Virology, medicine, Animals, Humans, Point Mutation, Electrophoretic mobility shift assay, Promoter Regions, Genetic, 030304 developmental biology, Aged, Early Growth Response Protein 1, rs653765, 0303 health sciences, business.industry, Organ dysfunction, Membrane Proteins, ADAM10, Middle Aged, medicine.disease, QR1-502, 3. Good health, Mice, Inbred C57BL, 030220 oncology & carcinogenesis, Case-Control Studies, Immunology, Disease Progression, Female, medicine.symptom, Amyloid Precursor Protein Secretases, business, Chromatin immunoprecipitation, Research Article, Protein Binding |
| الوصف: | Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases. Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. In vitro results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the ADAM10 gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention in vivo decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model. |
| اللغة: | English |
| تدمد: | 2150-7511 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::93ce60ae2f9e2200ac1181d092ffd83e https://journals.asm.org/doi/10.1128/mBio.01663-19 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....93ce60ae2f9e2200ac1181d092ffd83e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21507511 |
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