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）： 该应用程序的目的是建立独立研究生涯 慢性肺疾病研究中的候选人，包括 影响囊性纤维化（CF）的个体。 候选人是儿科 肺同伴的职业目标是制定一个积极的计划 与疾病有关的基础研究是医学院的教职员工。 这 培训环境是赞助商的实验室，塞缪尔·米勒（Samuel Miller）博士 华盛顿大学医学院和CF中心 西雅图的儿童医院和地区医疗中心，由 共同赞助商罗纳德·吉布森（Ronald Gibson）博士。 拟议的项目旨在澄清 慢性肺部感染和炎症的分子机制 患有CF的人 机会性病原体铜绿假单胞菌（PA） 感染大多数CF患者的肺，经常（但不是总是） 造成严重的进行性肺部损伤和过早死亡。 研究 PA与CF肺之间的相互作用是必须了解的 促进或允许CF肺部感染的细胞过程，精确 PA与肺部细胞相互作用以引起气道损害的手段。 这 脂多糖（LPS）的结构，是主要成分 革兰氏阴性细菌表面似乎在这两种情况下都起着关键作用 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对实验室和临床分离株的抗性 抗菌肽（宿主先天免疫的关键成分）与 脂质的结构改变了LPS的部分。 而且， 调节LPS修饰酶的PA基因座的突变会影响 抗菌肽抗性表型。 微生物阶段 因此，项目试图定义该推定抗性所需的PA基因 机制，并使用抗菌剂鉴定潜在的抑制剂 耐肽菌株。 该项目的人类阶段建立在 临床观察，某些患有严重CF基因型和 慢性PA气道感染仍然具有最小的肺部疾病。 一个 病例对照设计将用于测试多态性的假设 在先天免疫中，基因可能会限制CF肺部疾病。 那些先天免疫基因 编码LPS受体是基于CF修饰符基因座的领先候选者 最近的发现CF特异性PA LPS结构增加了 炎症活动。 当LPS受体变体的患病率在 轻度和重度CF肺疾病，将在细胞中测定受体功能 LPS信号的文化模型。 将先天免疫基因识别为修饰符 CF肺表型可能提出了治疗炎症的新途径 CF气道感染的后果。

项目成果

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

• DOI: 10.1371/journal.pone.0054205
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rada B;Jendrysik MA;Pang L;Hayes CP;Yoo DG;Park JJ;Moskowitz SM;Malech HL;Leto TL
• 通讯作者: Leto TL

Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment.

囊性纤维化肺病：遗传影响、微生物相互作用和放射学评估。

• DOI: 10.1007/s00247-005-1445-3
• 发表时间: 2005
• 期刊: Pediatric radiology
• 影响因子: 2.3
• 作者: Moskowitz,SamuelM;Gibson,RonaldL;Effmann,EricL
• 通讯作者: Effmann,EricL

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

• DOI: 10.1097/gim.0b013e31818e55a2
• 发表时间: 2008-12
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Moskowitz SM;Chmiel JF;Sternen DL;Cheng E;Gibson RL;Marshall SG;Cutting GR
• 通讯作者: Cutting GR