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Lung Endothelial Aß in infectious proteinopathy

肺内皮 A 与感染性蛋白病的关系

基本信息

批准号：
10207758
负责人：
Troy Stevens
金额：
$ 38.5万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207758
关键词：
Abeta synthesis Address Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Bacteria CRISPR/Cas technology Cells Characteristics Cleaved cell Clinical Research Complex Critical Illness Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic Nucleotides Cytotoxin Data Death Rate Endothelial Cells Endothelium Functional disorder GTPase-Activating Proteins Generations Hospitals Infection Intensive Care Units Knowledge Length of Stay Lung Membrane Methylation MicroRNAs Morbidity - disease rate Multiprotein Complexes Nosocomial pneumonia Organ Patients Phosphorylation Play Prions Process Production Property Protein Kinase Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Reporting Role Severities Specificity Testing Type III Secretion System Pathway Virulence Factors antimicrobial beta secretase cell injury cytotoxic cytotoxicity enzyme activity exoenzyme gamma secretase mortality pathogen presenilin-1 prevent prion-like protein expression protein function sequential proteolysis transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Pathogens responsible for nosocomial pneumonia elicit production of lung endothelial cell amyloids. These amyloids can have antimicrobial properties and be beneficial to the host, or they can have cytotoxic properties and be detrimental to the host. In the latter case, endothelial-derived amyloids may contribute to end organ dysfunction in the aftermath of critical illness. Bacterial virulence factors, such as the Pseudomonas aeruginosa type III secretion system effectors, and most notably exoenzyme Y, convert endothelial amyloids from antimicrobial to cytotoxic species. Amyloid-beta (Aβ) is one of the cytotoxic amyloids generated following endothelial infection. Aβ is released from endothelium where it becomes a transmissible and self-replicating prion cytotoxin. Our preliminary data reveals that γ-secretase activating protein plays a critical role in generating cytotoxic Aβ. We found γ-secretase activating protein expression in endothelial cells using non- biased microarray, RNAseq, methylation and miRNA screens, and confirmed protein expression and function in microvascular endothelium. γ-secretase activating protein deletion prevented formation of the cytotoxic Aβ species. Rather, following γ-secretase activating protein deletion the Pseudomonas aeruginosa- and exoenzyme Y-induced Aβ had antimicrobial properties. Exoenzyme Y is a promiscuous nucleotidyl cyclase that results in protein kinase A activation, which may phosphorylate Aβ necessary to increase its cytotoxic activity. These data suggest production of cytotoxic Aβ is due to two inter-related mechanisms, including an increase in γ-secretase activating protein function and the phosphorylation of Aβ once it is produced. Hence, this proposal tests the hypothesis that exoenzyme Y promotes the production of cytotoxic Aβ, dependent upon γ-secretase activating protein.

项目总结/文摘