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：
10650303
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/10650303
关键词：
Abeta synthesis Address Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Bacteria CRISPR/Cas technology Cells Characteristics Clinical Research Critical Illness Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic Nucleotides Cytoprotection 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 Vascular Endothelium Virulence Factors antimicrobial beta secretase beta-site APP cleaving enzyme 1 cell injury cytotoxic cytotoxicity enzyme activity exoenzyme gamma secretase mortality pathogen presenilin-1 prevent prion-like protein B 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.

项目摘要/摘要负责医院肺炎的病原体会引起肺内皮细胞淀粉样蛋白的产生。这些淀粉样蛋白可以具有抗菌特性，对宿主有益，也可以具有细胞毒性特性并确定为主机。在后一种情况下，内皮衍生的淀粉样蛋白可能有助于结束器官危重疾病后的功能障碍。细菌病毒因子，例如假单胞菌铜绿III型分泌系统效果，最著名的是exoenzyme y，转化内皮淀粉样蛋白从抗菌剂到细胞毒性物种。淀粉样蛋白β（Aβ）是产生的细胞毒性淀粉样蛋白之一内皮感染。 Aβ从内皮释放，在内皮变为可传播和自我复制 prion细胞毒素。我们的初步数据表明，γ-分泌酶激活蛋白在产生细胞毒性Aβ。我们发现使用非 - 偏置微阵列，RNASEQ，甲基化和miRNA筛选，并确认蛋白质表达和功能在微血管森林中。 γ-分泌酶激活蛋白缺失阻止了细胞毒性Aβ的形成物种。相反，遵循γ-分泌酶激活蛋白缺失，铜绿假单胞菌和外酶Y诱导的Aβ具有抗菌特性。外酶是一种混杂的核苷酸环化酶导致蛋白激酶A激活，这可能会磷酸化Aβ以增加其细胞毒性活性。这些数据表明，细胞毒性Aβ的产生是由于两种相互关联的机制，包括增加产生γ-分泌酶激活蛋白功能和Aβ的磷酸化。因此，这个建议检验外酶y促进细胞毒性Aβ的产生的假设，取决于γ-分泌酶激活蛋白。