Host-Pathogen Interactions in Cystic Fibrosis

囊性纤维化中宿主与病原体的相互作用

• 批准号: 6928462
• 负责人: SAMUEL M MOSKOWITZ
• 金额: $ 12.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-05 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928462
• 关键词: CD14 molecule; Pseudomonas aeruginosa; bacteria infection mechanism; bactericidal immunity; chemical structure function; cystic fibrosis; genetic strain; genetic susceptibility; human subject; lipopolysaccharides; lung disorder; molecular pathology; patient oriented research; respiratory infections; spirometry; sputum

DESCRIPTION (provided by applicant): The goal of this application is to establish the independent research career of the candidate in the study of chronic lung disease, including that affecting individuals with cystic fibrosis (CF). The candidate is a pediatric pulmonary fellow with the career goal of developing an active program of disease-related basic research as a faculty member at a medical school. The training environments are the laboratory of the sponsor, Dr. Samuel Miller, at the University of Washington School of Medicine, and the CF Center at Children's Hospital and Regional Medical Center in Seattle, directed by the co-sponsor, Dr. Ronald Gibson. The proposed project seeks to clarify molecular mechanisms underlying chronic lung infection and inflammation in individuals with CF. The opportunistic pathogen Pseudomonas aeruginosa (PA) infects the lungs of most individuals with CF, frequently (but not invariably) causing severe progressive lung injury and premature death. Study of the interaction between PA and the CF lung is necessary to understand both the cellular processes that promote or permit CF lung infection, and the precise means by which PA interacts with lung cells to cause airway damage. The structure of lipopolysaccharide (LPS), the principal constituent of Gram-negative bacterial surfaces, appears to play a pivotal role in both microbial and human aspects of this interaction. The candidate's preliminary results indicate that resistance of laboratory and clinical isolates of PA to antimicrobial peptides (key components of host innate immunity) correlates with alterations in the structure of the lipid A moiety of LPS. Moreover, mutation of a PA locus that regulates LPS-modifying enzymes influences the antimicrobial peptide resistance phenotype. The microbiological phase of the project thus seeks to define PA genes necessary for this putative resistance mechanism, and to identify potential inhibitors using antimicrobial peptide-resistant strains. The human phase of the project builds on the clinical observation that some individuals with a severe CF genotype and chronic PA airway infection nevertheless have minimal lung disease. A case-control design will be utilized to test the hypothesis that polymorphisms in innate immune genes may limit CF lung disease. Those innate immune genes encoding the LPS receptor are leading candidates as CF modifier loci, based on the recent finding that CF-specific PA LPS structures have increased inflammatory activity. When prevalence of an LPS receptor variant differs in mild and severe CF lung disease, receptor function will be assayed in cell culture models of LPS signaling. Identifying innate immune genes as modifiers of the CF lung phenotype may suggest new avenues for treating the inflammatory consequences of CF airway infection.

描述（由申请人提供）： 该应用程序的目标是建立独立的研究生涯 慢性肺病研究的候选人，包括 影响囊性纤维化 (CF) 患者。 候选人是一名儿科 肺研究员，其职业目标是制定一项积极的计划 作为医学院的教员进行疾病相关的基础研究。 这 培训环境是赞助商 Samuel Miller 博士的实验室，位于 华盛顿大学医学院和 CF 中心 西雅图儿童医院和地区医疗中心，由 共同发起人罗纳德·吉布森博士。 拟议项目旨在澄清 慢性肺部感染和炎症的分子机制 患有 CF 的个体。 机会致病菌铜绿假单胞菌 (PA) 大多数 CF 患者的肺部经常（但并非总是）感染 导致严重的进行性肺损伤和过早死亡。 研究的 PA 和 CF 肺之间的相互作用对于理解两者是必要的 促进或允许 CF 肺部感染的细胞过程，以及精确的 PA 与肺细胞相互作用导致气道损伤的方式。 这 脂多糖（LPS）的结构，其主要成分 革兰氏阴性细菌表面似乎在两者中都发挥着关键作用 这种相互作用的微生物和人类方面。 候选人的初步 结果表明，PA 的实验室和临床分离株对 抗菌肽（宿主先天免疫的关键成分）相关 LPS 脂质 A 部分的结构发生改变。 而且， 调节 LPS 修饰酶的 PA 位点突变会影响 抗菌肽耐药表型。 微生物阶段 因此，该项目试图定义这种假定的抗性所必需的 PA 基因 机制，并使用抗菌药物识别潜在的抑制剂 肽抗性菌株。 该项目的人力阶段建立在 临床观察发现，一些具有严重 CF 基因型的个体 然而，慢性 PA 气道感染很少有肺部疾病。 一个 将利用病例对照设计来检验多态性的假设 先天免疫基因可能会限制 CF 肺部疾病。 那些先天免疫基因 编码 LPS 受体的 CF 修饰基因座是主要候选者，基于 最近发现 CF 特异性 PA LPS 结构有所增加 炎症活动。 当 LPS 受体变异体的流行率存在差异时 轻度和重度 CF 肺部疾病，将在细胞中检测受体功能 LPS 信号传导的培养模型。 识别先天免疫基因作为修饰因子 CF肺表型的研究可能为治疗炎症提供新途径 CF 气道感染的后果。

项目成果

Pandoraea bacteremia in a cystic fibrosis patient with associated systemic illness.

患有相关全身性疾病的囊性纤维化患者的潘多拉菌菌血症。

• 发表时间: 2004-09
• 作者: Johnson, Lindsey N;Han, Jin;Moskowitz, Samuel M;Burns, Jane L;Qin, Xuan;Englund, Janet A
• 通讯作者: Englund, Janet A

Polymyxin resistance of Pseudomonas aeruginosa phoQ mutants is dependent on additional two-component regulatory systems.

铜绿假单胞菌 phoQ 突变体的多粘菌素抗性依赖于额外的两部分调节系统。

• 发表时间: 2013-05
• 影响因子: 4.9
• 作者: Gutu, Alina D;Sgambati, Nicole;Strasbourger, Pnina;Brannon, Mark K;Jacobs, Michael A;Haugen, Eric;Kaul, Rajinder K;Johansen, Helle Krogh;Hoiby, Niels;Moskowitz, Samuel M
• 通讯作者: Moskowitz, Samuel M

Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders.

囊性纤维化和 CFTR 相关疾病的临床实践和遗传咨询。

• 发表时间: 2008-12
• 作者: Moskowitz, Samuel M;Chmiel, James F;Sternen, Darci L;Cheng, Edith;Gibson, Ronald L;Marshall, Susan G;Cutting, Garry R
• 通讯作者: Cutting, Garry R

Colistin susceptibility testing: evaluation of reliability for cystic fibrosis isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

粘菌素敏感性测试：铜绿假单胞菌和嗜麦芽寡养单胞菌囊性纤维化分离株的可靠性评估。

• 发表时间: 2010-07
• 作者: Moskowitz, Samuel M;Garber, Elizabeth;Chen, Yunhua;Clock, Sarah A;Tabibi, Setareh;Miller, Amanda K;Doctor, Michael;Saiman, Lisa
• 通讯作者: Saiman, Lisa

Pyocyanin-enhanced neutrophil extracellular trap formation requires the NADPH oxidase.

绿脓素增强中性粒细胞胞外陷阱的形成需要 NADPH 氧化酶。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Rada, Balázs;Jendrysik, Meghan A;Pang, Lan;Hayes, Craig P;Yoo, Dae;Park, Jonathan J;Moskowitz, Samuel M;Malech, Harry L;Leto, Thomas L
• 通讯作者: Leto, Thomas L