Systematic analysis of Proteus mirabilis transcriptional regulators that drive uropathogenesis
驱动尿路病理发生的奇异变形杆菌转录调节因子的系统分析
基本信息
- 批准号:10594401
- 负责人:
- 金额:$ 4.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdherenceAgarAntibiotic ResistanceBacteriaBiochemicalBioinformaticsBiological AssayBiologyBladderBladder CalculiCathetersCell physiologyComplementCuesData SetDevelopmentEnvironmentEssential GenesFlagellaFutureGenesGenetic TranscriptionGenomeGoalsGrowthHarvestHealthcare SystemsHourIn VitroIndividualInfectionIronKnowledgeLearningLibrariesLiteratureMaintenanceMediatingMethodologyMethodsMicrobial BiofilmsMolecularMusMutagenesisNamesNatural ResistanceNosocomial InfectionsNutrientOrganismOutcomeOutputPathogenesisPatientsPhenotypePhysiciansPlasmidsPolymyxinsProductionProteus mirabilisPublishingQuantitative Reverse Transcriptase PCRRegulonSourceSystemTechniquesTestingTetracycline ResistanceTherapeuticToxinUnited StatesUreaseUrinary CalculiUrinary tractUrinary tract infectionUrinationUrineVaccinesVirulenceVirulence FactorsVisitbioinformatics toolcatheter associated UTIcomparativecostexperimental studyfitnessfollow-upgenetic approachgenome-widein vivoinducible gene expressioninterestknowledge basemembermouse modelmutantnovelnovel therapeuticspathogenpromoterresponsescreeningtargeted treatmenttranscription factortranscriptome sequencingtranscriptomicstransposon sequencinguptakevector
项目摘要
ABSTRACT
Urinary Tract Infections (UTIs) are common infections that represent a significant burden on healthcare
systems worldwide. In 2006 alone, UTIs were the source of 11 million physician visits and cost the
United States over $3.5 billion. A significant portion of these infections are Catheter-Associated UTIs
(CAUTIs), accounting for up to 40% of hospital acquired infections globally. A major cause of CAUTIs
is Proteus mirabilis, an understudied Gram-negative member of the Enterobacterales order. This
organism is most noted for its ability to swarm on agar and form urinary stones in infected patients.
Previous studies have used a mouse model of UTI to identify factors that contribute to fitness and
virulence in the urinary tract. While these datasets strongly implicate transcriptional regulators, there is
much to learn about transcriptional networks in this species. Toward this end, I have developed the
framework to employ Transcriptional Regulator Induced Phenotype (TRIP) screening to identify
specific regulators that contribute to uropathogenesis. TRIP leverages a library of strains containing
inducible expression constructs that each encode a single regulator. Pools of these strains will be
inoculated into the mouse model of UTI to assess comparative fitness. Sequencing and bioinformatic
analyses will be used to assess relative fitness of TRIP strains and identify strains with a competitive
edge in the bladder environment. After identifying these key regulators, I aim to define the downstream
regulatory networks using RNA-sequencing and employ genetic approaches, biochemical assays, and
the murine model of UTI to ascertain the molecular mechanisms behind the fitness advantage. Using
a systematic bioinformatics approach, I have identified 232 putative transcriptional regulators in the
HI4320 genome. Only 3 of these regulators have defined regulons published in the literature. Thus far,
35/232 (15%) of the constructs have been generated. During library construction, I have validated the
TRIP framework using a variety of techniques (growth curves, qRT-PCR, and plasmid maintenance
experiments). These studies indicate that stable expression of regulators is not broadly toxic, the
selected promoter is inducible, and the construct vectors are stable both in vitro and in vivo. This project
represents the first in vivo application of TRIP and will identify regulators and characterize key
regulatory networks that drive Proteus mirabilis uropathogenesis.
摘要
尿路感染(UTI)是一种常见的感染,给医疗保健带来了巨大的负担
世界各地的系统。仅在2006年,尿路感染就是1100万医生就诊的来源,并使
美国超过35亿美元。这些感染中很大一部分是与导管相关的尿路感染
(CAUTIs),占全球医院获得性感染的40%。CAUTIs的一个主要原因
是奇异变形杆菌,是肠杆菌目中一种未被充分研究的革兰氏阴性菌。这
细菌最著名的是它在琼脂上聚集并在感染患者身上形成尿结石的能力。
以前的研究已经使用尿路感染的小鼠模型来确定有助于健康和
尿路中的毒力。虽然这些数据集强烈暗示了转录调控因子,但
关于这个物种的转录网络有很多需要了解的。为此,我开发了
利用转录调节因子诱导表型(TRIP)筛查进行鉴定的框架
导致尿路致病的特定调节因子。TRIP利用了一个包含以下内容的菌株库
可诱导表达构建体,每个表达构建体编码一个单一的调节子。这些菌株的池将是
接种于UTI小鼠模型,评估其相对适合性。测序和生物信息学
分析将用于评估TRIP菌株的相对适合度,并鉴定具有竞争性的菌株
在膀胱环境中的边缘。在确定了这些关键监管机构之后,我的目标是定义下游
使用RNA测序的调控网络,并使用遗传方法、生化分析和
UTI的小鼠模型,以确定健康优势背后的分子机制。vbl.使用
通过系统的生物信息学方法,我已经确定了232个假定的转录调控因子
HI4320基因组。在这些监管机构中,只有3家定义了文献中公布的监管规定。到目前为止,
已经生成了35/232(15%)的构建体。在图书馆建设过程中,我已经验证了
使用多种技术的TRIP框架(生长曲线、qRT-PCR和质粒维护
实验)。这些研究表明,稳定表达调节剂没有广泛的毒性,
所选择的启动子是可诱导的,构建的载体在体内外都是稳定的。这个项目
代表了TRIP的第一个活体应用,并将确定调节器和表征关键
驱动奇异变形杆菌泌尿致病的调控网络。
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 }}
Madison Jane Fitzgerald其他文献
Madison Jane Fitzgerald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('Madison Jane Fitzgerald', 18)}}的其他基金
Systematic analysis of Proteus mirabilis transcriptional regulators that drive uropathogenesis
驱动尿路病理发生的奇异变形杆菌转录调节因子的系统分析
- 批准号:
10386534 - 财政年份:2022
- 资助金额:
$ 4.13万 - 项目类别:
相似海外基金
An innovative, AI-driven prehabilitation platform that increases adherence, enhances post-treatment outcomes by at least 50%, and provides cost savings of 95%.
%20创新、%20AI驱动%20康复%20平台%20%20增加%20依从性、%20增强%20治疗后%20结果%20by%20at%20至少%2050%、%20和%20提供%20成本%20节省%20of%2095%
- 批准号:
10057526 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Grant for R&D
Improving Repositioning Adherence in Home Care: Supporting Pressure Injury Care and Prevention
提高家庭护理中的重新定位依从性:支持压力损伤护理和预防
- 批准号:
490105 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Operating Grants
I-Corps: Medication Adherence System
I-Corps:药物依从性系统
- 批准号:
2325465 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Standard Grant
Unintrusive Pediatric Logging Orthotic Adherence Device: UPLOAD
非侵入式儿科记录矫形器粘附装置:上传
- 批准号:
10821172 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Nuestro Sueno: Cultural Adaptation of a Couples Intervention to Improve PAP Adherence and Sleep Health Among Latino Couples with Implications for Alzheimer’s Disease Risk
Nuestro Sueno:夫妻干预措施的文化适应,以改善拉丁裔夫妇的 PAP 依从性和睡眠健康,对阿尔茨海默病风险产生影响
- 批准号:
10766947 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
CO-LEADER: Intervention to Improve Patient-Provider Communication and Medication Adherence among Patients with Systemic Lupus Erythematosus
共同领导者:改善系统性红斑狼疮患者的医患沟通和药物依从性的干预措施
- 批准号:
10772887 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Pharmacy-led Transitions of Care Intervention to Address System-Level Barriers and Improve Medication Adherence in Socioeconomically Disadvantaged Populations
药房主导的护理干预转型,以解决系统层面的障碍并提高社会经济弱势群体的药物依从性
- 批准号:
10594350 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Antiretroviral therapy adherence and exploratory proteomics in virally suppressed people with HIV and stroke
病毒抑制的艾滋病毒和中风患者的抗逆转录病毒治疗依从性和探索性蛋白质组学
- 批准号:
10748465 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Improving medication adherence and disease control for patients with multimorbidity: the role of price transparency tools
提高多病患者的药物依从性和疾病控制:价格透明度工具的作用
- 批准号:
10591441 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Development and implementation of peer-facilitated decision-making and referral support to increase uptake and adherence to HIV pre-exposure prophylaxis in African Caribbean and Black communities in Ontario
制定和实施同行协助决策和转介支持,以提高非洲加勒比地区和安大略省黑人社区对艾滋病毒暴露前预防的接受和依从性
- 批准号:
491109 - 财政年份:2023
- 资助金额:
$ 4.13万 - 项目类别:
Fellowship Programs