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:10438793
- 负责人:
- 金额:$ 38.5万
- 依托单位:
- 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:
- 关键词:Abeta synthesisAddressAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorBacteriaCRISPR/Cas technologyCellsCharacteristicsClinical ResearchComplexCritical IllnessCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic GMPCyclic NucleotidesCytotoxinDataDeath RateEndothelial CellsEndotheliumFunctional disorderGTPase-Activating ProteinsGenerationsHospitalsInfectionIntensive Care UnitsKnowledgeLength of StayLungMembraneMethylationMicroRNAsMorbidity - disease rateMultiprotein ComplexesNosocomial pneumoniaOrganPatientsPhosphorylationPlayPrionsProcessProductionPropertyProtein KinaseProteinsPseudomonas aeruginosaPseudomonas aeruginosa infectionPublishingReportingRoleSeveritiesSpecificityTestingType III Secretion System PathwayVirulence Factorsantimicrobialbeta secretasecell injurycytotoxiccytotoxicityenzyme activityexoenzymegamma secretasemortalitypathogenpresenilin-1preventprion-likeprotein expressionprotein functionsequential proteolysistranscriptome 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
引起医院获得性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
对寄主不利。在后一种情况下,内皮源性淀粉样蛋白可能对终末器官有贡献
危重疾病后的功能障碍。细菌毒力因子,如假单胞菌
铜绿假单胞菌III型分泌系统效应器,最显著的是外酶Y,转化内皮淀粉样蛋白
从抗菌物质到细胞毒性物质。淀粉样β蛋白(Aβ)是一种细胞毒性淀粉样蛋白
内皮细胞感染。β从内皮细胞中释放出来,在那里它成为可传播和自我复制的
普恩细胞毒素。我们的初步数据显示,γ-分泌酶激活蛋白在
产生细胞毒性的A-β。我们发现γ-分泌酶激活蛋白在内皮细胞中的表达
偏置微阵列、RNAseq、甲基化和miRNA筛选,并确认蛋白质表达和功能
在微血管内皮细胞。γ-分泌酶激活蛋白缺失阻止细胞毒素Aβ的形成
物种。相反,在γ分泌酶激活蛋白缺失后,铜绿假单胞菌-和
胞外酶Y诱导的A-β具有抗菌特性。外切酶Y是一种杂乱的核苷酸环化酶
导致蛋白激酶A激活,这可能使Aβ磷酸化,从而增加其细胞毒活性。
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
γ-分泌酶激活蛋白的功能和A-β一旦产生就被磷酸化。因此,这项提议
验证外酶Y依赖于β分泌酶促进细胞毒素Aγ产生的假说
激活蛋白质。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Troy Stevens其他文献
Troy Stevens的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Troy Stevens', 18)}}的其他基金
Soluble adenylyl cyclases in lung endothelial tauopathy
肺内皮tau蛋白病中的可溶性腺苷酸环化酶
- 批准号:
10636060 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
Lung Endothelial Aß in infectious proteinopathy
肺内皮 A 与感染性蛋白病的关系
- 批准号:
10650303 - 财政年份:2020
- 资助金额:
$ 38.5万 - 项目类别:
Lung Endothelial Aß in infectious proteinopathy
肺内皮 A 与感染性蛋白病的关系
- 批准号:
10207758 - 财政年份:2020
- 资助金额:
$ 38.5万 - 项目类别:
Determinants of Pulmonary Endothelial Cell Function Conf
肺内皮细胞功能的决定因素
- 批准号:
6707800 - 财政年份:2004
- 资助金额:
$ 38.5万 - 项目类别:
Training in Cell Signaling and Lung Pathobiology
细胞信号传导和肺部病理学培训
- 批准号:
9061755 - 财政年份:2004
- 资助金额:
$ 38.5万 - 项目类别:
Training in Cell Signaling and Lung Pathobiology
细胞信号传导和肺部病理学培训
- 批准号:
8607821 - 财政年份:2004
- 资助金额:
$ 38.5万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 38.5万 - 项目类别:
Research Grant