权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pseudomonas Aeruginosa Early CF Adaptive Changes: A Translational Study

铜绿假单胞菌早期 CF 适应性变化：一项转化研究

基本信息

批准号：
8598103
负责人：
Lucas R Hoffman
金额：
$ 10.01万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-21 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598103
关键词：
Addendum Address Age Ancillary Study Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Antibiotics Bacteria Caucasians Caucasoid Race Characteristics Child Chronic Clinical Clinical Data Clinical Research Clinical Trials Cohort Studies Color Cystic Fibrosis Data Databases Development Disease Disease Progression Enrollment Environment Epidemiology Functional disorder Funding Genes Goals Gram-Negative Bacteria Growth Height Hereditary Disease Hospitalization In Vitro Infection Inflammatory Response Intervention Lactamase Lead Life Life Expectancy Link Liquid substance Longevity Longitudinal Studies Lung Lung diseases Measures Mentorship Metabolic Methods Microbiology Mutation Natural History Nitrates Observational Study Outcome Patients Phenotype Physicians Pigments Population Prevalence Production Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Quality of life Regimen Research Research Training Respiratory System Respiratory physiology Respiratory tract structure Risk Factors Role Subgroup Testing Therapeutic Time Training Translational Research Weight advanced disease career cell motility children with cystic fibrosis clinically relevant cohort cystic fibrosis airway cystic fibrosis patients early cystic fibrosis follow-up inhibitor/antagonist microbial mutant novel pathogen prevent prospective public health relevance respiratory translational study

项目摘要

DESCRIPTION (provided by applicant): Lung disease is the primary determinant of life expectancy and quality of life among people with the genetic disease cystic fibrosis (CF). The opportunistic Gram-negative bacterium Pseudomonas aeruginosa infects the respiratory tracts of most patients with CF, and infection with this pathogen is clearly associated with worse respiratory outcomes. P. aeruginosa infects CF airways early in life. Over many years, bacteria adapt to the CF airway environment and stimulate inflammatory responses that are ineffective in eradicating the infection, yet damage airways. The development of strategies to prevent P. aeruginosa colonization and eliminate chronic infection will require an understanding of the natural history of the bacterial contribution to CF lung disease. This proposal describes a four-year plan to further establish the independent, translational research career for the candidate. In particular, the candidate, a trained physician and microbiologist, will continue his clinical research training and focus his time on his funded, collaborative project to define the natural history of P. aeruginosa changes during early CF airway infection. This project uses the P. aeruginosa clinical isolates, linked clinical data, and unique clinical research mentorship opportunities available from two locally-led, national studies of CF microbiology, the Early Antipseudomonal Therapy in Cystic Fibrosis studies (EPIC). Specifically, this project will define the clinical relevance of infection with P. aeruginosa carrying a newly-identified adaptive change: inactivating mutation in the gene encoding the major transcriptional regulator LasR. This mutation was associated in our preliminary studies with accelerated lung function decline. Perhaps related to this finding, preliminary evidence suggests that LasR mutation leads to increased resistance to the antibiotics used most often in CF therapy. Conversely, LasR mutants are more susceptible in vitro to at least two classes of metabolic inhibitors, suggesting alternative therapeutic strategies for patients infected with these isolates. Thus, the emergence of LasR mutation during chronic P. aeruginosa CF airway infections may serve as a marker for advancing disease, and novel therapies could be developed for patients carrying these adaptive mutants. However, to address the utility of these approaches, our preliminary epidemiologic findings must be validated in a larger, multicenter population. We aim to define the prevalence and associated clinical features of LasR mutant P. aeruginosa infection among the young children enrolled in the EPIC trials, to test the hypothesis that LasR mutation occurs relatively commonly and early during P. aeruginosa CF infections, and is associated with preceding antibiotic exposure, accelerated decline in lung function, and more frequent respiratory exacerbations. Here, we also propose to compare results concerning LasR mutation with those for other common P. aeruginosa CF adaptive changes in this population. The results of this study will clarify the natural history of CF lung disease, and may lead to improvements in current CF therapeutic regimens. PUBLIC HEALTH RELEVANCE: Cystic fibrosis (CF) is the most common genetic disease of Caucasians, and people with CF die at a median age of 37 years from chronic lung infections that limit their quality and length of life. This proposal describes a four-year plan to further establish the translational research career of the candidate, focused on the pathophysiology of chronic CF lung infections with the long-term goals of identifying and developing better treatments for this devastating disease. The project described here will define the differences among the bacteria that cause CF lung infections, and the relationship between these bacterial characteristics and lung disease progression, as a critical next step towards these goals.

描述(由申请人提供)：肺部疾病是遗传性囊性纤维化(CF)患者预期寿命和生活质量的主要决定因素。机会革兰氏阴性杆菌铜绿假单胞菌感染大多数CF患者的呼吸道，这种病原体的感染显然与较差的呼吸结局有关。铜绿假单胞菌在生命早期感染慢性支气管炎。多年来，细菌适应了CF的呼吸道环境，并刺激了炎症反应，这些反应在根除感染方面无效，但会损害呼吸道。制定预防铜绿假单胞菌定植和消除慢性感染的策略将需要了解细菌对慢性肺病的自然历史贡献。这份提案描述了一项四年计划，以进一步为候选人建立独立的、翻译的研究生涯。特别是，候选人是一名训练有素的内科医生和微生物学家，他将继续他的临床研究培训，并将他的时间集中在他的资助的合作项目上，以确定铜绿假单胞菌在早期CF呼吸道感染期间变化的自然历史。该项目使用了铜绿假单胞菌的临床分离株、相关的临床数据以及两项地方主导的全国性CF微生物学研究-囊性纤维化早期抗假单胞菌疗法(EPIC)-提供的独特的临床研究指导机会。具体地说，该项目将定义感染携带新发现的适应性变化的铜绿假单胞菌的临床相关性：编码主要转录调节因子LasR的基因的失活突变。在我们的初步研究中，这种突变与肺功能加速下降有关。可能与这一发现有关，初步证据表明，LasR突变导致对CF治疗中最常用的抗生素的耐药性增加。相反，LasR突变株在体外对至少两类代谢抑制剂更敏感，这为感染这些菌株的患者提供了替代治疗策略。因此，在慢性铜绿假单胞菌Cf呼吸道感染过程中LasR突变的出现可能作为疾病进展的标志，并且可以为携带这些适应性突变的患者开发新的治疗方法。然而，为了解决这些方法的有效性，我们的初步流行病学发现必须在更大的多中心人群中得到验证。我们的目标是确定在EPIC试验中登记的幼儿中LasR突变铜绿假单胞菌感染的患病率和相关的临床特征，以检验LasR突变在铜绿假单胞菌感染期间相对常见和早期发生的假设，并与先前的抗生素暴露、肺功能加速下降和更频繁的呼吸恶化有关。在这里，我们还建议将有关LasR突变的结果与该人群中其他常见的铜绿假单胞菌Cf适应性变化的结果进行比较。这项研究的结果将阐明慢性肺病的自然病史，并可能导致目前的慢性肺病治疗方案的改进。公共卫生相关性：囊性纤维化(CF)是高加索人最常见的遗传病，患有囊性纤维化的人死于慢性肺部感染，年龄中值为37岁，这些感染限制了他们的生命质量和长度。这份提案描述了一个四年计划，以进一步建立候选人的翻译研究生涯，重点是慢性肺纤维化肺部感染的病理生理学，长期目标是确定和开发这种毁灭性疾病的更好治疗方法。这里描述的项目将定义引起肺部感染的细菌之间的差异，以及这些细菌特征和肺部疾病进展之间的关系，作为实现这些目标的关键下一步。