Identification of Bacterial Genes that Disrupt Host Proteostasis

鉴定破坏宿主蛋白质稳态的细菌基因

基本信息

批准号：
10224099
负责人：
Daniel Milosz Czyz
金额：
$ 7.44万
依托单位：
UNIVERSITY OF FLORIDA
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：
2020-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224099
关键词：
Affect Aging Alzheimer&apos s Disease Amyloid Amyotrophic Lateral Sclerosis Antibiotics Attenuated Bacteria Bacterial Genes Bacterial Genome Caenorhabditis elegans Databases Development Disease Environment Genes Goals Human Human Genome Human Microbiome Human body Huntington Disease Infection Intestines Klebsiella pneumoniae Knock-out Libraries Link Modeling Muscle Muscle function Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Organ Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Patients Physiological Play Population Process Protein Conformation Proteins Pseudomonas aeruginosa Regulation Research Role Signaling Molecule Source Therapeutic Tissues commensal bacteria dysbiosis effective therapy experimental study genome wide screen gut microbiota mutant neuron loss opportunistic pathogen peptide hormone polyglutamine prophylactic protein aggregation protein biomarkers protein folding protein misfolding proteostasis

项目摘要

Protein conformational diseases (PCDs) are characterized by a progressive loss of neuronal or muscle function due to protein misfolding and aggregation, a common feature among diseases such as Alzheimer's, Parkinson's, Huntington's, or Lou Gehrig's disease. The exact factors that influence PCDs are not known. Recent evidence suggests that bacteria may contribute to the pathogenesis of these neurodegenerative diseases. To better understand the influence of bacteria on protein homeostasis (proteostasis), we are studying the effect of bacterial colonization of the Caenorhabditis elegans gut on protein aggregation in the intestine and other tissues. In a screen of 52 of the most common human pathogenic-commensal bacteria, we found two Gram-negative species, Pseudomonas aeruginosa and Klebsiella pneumoniae, that enhanced protein aggregation in the intestine by nearly five-fold; these two strains also affect protein aggregation in the muscle. Both species are part of the normal human microbiome and are known opportunistic pathogens. An increase in the abundance of these bacteria within the human gut was previously linked with the enhanced progression of neurodegenerative diseases. Collectively, these results suggest that intestinal bacteria affect the host folding environment; however, which bacterial factors are responsible for the enhancement of aggregation remains unknown. As such, we propose to screen genome-wide mutant libraries of P. aeruginosa and K. pneumoniae for genes that will abolish the enhancement of protein aggregation upon colonization of the C. elegans intestine. Identification of bacterial genes and pathways that are responsible for disruption of host proteostasis will provide a new mechanistic understanding of host-bacteria interaction that can provide a basis for the development of prophylactics, therapeutics, and biomarkers for PCDs.

蛋白质构象疾病（PCD）的特征是神经元或肌肉的逐渐丧失由于蛋白质错误折叠和聚集而引起的功能，这是阿尔茨海默氏症等疾病中的共同特征，帕金森氏症，亨廷顿或卢格里格氏病。影响PCD的确切因素尚不清楚。最近的证据表明，细菌可能有助于这些神经退行性疾病的发病机理。到更好地了解细菌对蛋白质稳态（蛋白质的）的影响，我们正在研究秀丽隐杆线虫肠道肠道的细菌定植在肠和其他组织中的蛋白质聚集上。在52个最常见的人类病原体细菌的屏幕中，我们发现了两个革兰氏阴性症物种，铜绿假单胞菌和肺炎克雷伯氏菌，增强了蛋白质聚集肠道近五倍；这两种菌株还会影响肌肉中的蛋白质聚集。这两个物种都是正常人类微生物组的一部分，是已知的机会病原体。丰富的以前，这些细菌与神经退行性的增强有关疾病。总的来说，这些结果表明肠道细菌会影响宿主折叠环境。然而，哪些细菌因素是导致聚集的增强的原因。因此，我们提议筛选铜绿假单胞菌和肺炎肺炎的全基因组突变库，以废除基因秀丽隐杆线虫肠道定植后，蛋白质聚集的增强。鉴定细菌负责破坏宿主蛋白质的基因和途径将提供一种新的机械了解可以为预防学的发展提供基础的宿主 - 细菌相互作用，治疗剂和PCD的生物标志物。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Automating Aggregate Quantification in Caenorhabditis elegans.

秀丽隐杆线虫聚合体定量自动化。

DOI：
10.3791/62997
发表时间：
2021
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Vaziriyan-Sani,AlfonsoS;Handy,RobertD;Walker,AlyssaC;Pagolu,CarolNavya;Enslow,SamanthaM;Czyż,DanielM
通讯作者：
Czyż,DanielM

Oh my gut! Is the microbial origin of neurodegenerative diseases real?