Functionality of CdrA and its processed forms within Pseudomonas aeruginosa biofilms

CdrA 的功能及其在铜绿假单胞菌生物膜中的加工形式

• 批准号: 10410640
• 负责人: Courtney Reichhardt
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410640
• 关键词: Address; Antibiotic Therapy; Antibiotics; Architecture; Bacteria; Bacterial Adhesins; Binding; Biochemical; Biological Assay; Catheters; Chronic; Clinical; Complement; Contact Lenses; DNA; Data; Development Plans; Extracellular Matrix; Faculty; Foundations; Funding; Future; Goals; Growth; Host Defense; Host Defense Mechanism; Immune response; Immune system; Infection; Integration Host Factors; International; Job Application; Laser Scanning Confocal Microscopy; Mechanics; Mediating; Mentors; Mentorship; Methods; Microbe; Microbial Biofilms; Microbiology; Microscopy; Mission; Modeling; Mucins; Nature; Peptide Hydrolases; Play; Positioning Attribute; Prevention; Process; Proteins; Proteolysis; Proteolytic Processing; Pseudomonas aeruginosa; Public Health; Research; Resistance; Scientist; Structure; Testing; Tissues; Training; United States National Institutes of Health; Work; antimicrobial; assault; base; biophysical chemistry; burn wound; career; career development; chronic infection; crosslink; cystic fibrosis patients; effective therapy; environmental change; experience; extracellular; faculty research; flexibility; improved; improved outcome; interdisciplinary approach; interest; intermolecular interaction; microbial community; multidisciplinary; pathogen; professor; programs; scaffold; solid state nuclear magnetic resonance; tool; urinary

PROJECT SUMMARY/ABSTRACT Microbial communities called biofilms are hallmarks of chronic infections. Pseudomonas aeruginosa is a model for biofilm study, and also is a pathogen that causes biofilm infections including of burns, wounds, urinary catheters, contact lenses, and the airways of patients with cystic fibrosis (CF). Biofilm microbes are encased in a mesh-like extracellular matrix that helps bacteria to evade host defenses and protects against external assaults such as antimicrobial treatment. A better understanding of biofilm matrix assembly is necessary to improve prevention and treatment of biofilm-involved infections. The long-term goal of this application and the candidate, Dr. Reichhardt, is to establish an independent research program focused on the nature and functional impact of intermolecular interactions in biofilm. Towards this goal, the immediate career objective of Dr. Reichhardt is to obtain an independent faculty position using the proposed research as the foundation of her job applications. The overall research objective of this application is to investigate the flexibility and control of matrix interactions of the key P. aeruginosa protein CdrA. Based on preliminary data, the hypothesis is that the biofilm functionality of CdrA can be expanded through enzymatic processing and binding to host factors, impacting biofilm stability. To test this hypothesis, two specific aims are proposed and will be investigated using Dr. Reichhardt’s unique multidisciplinary training in biophysical chemistry and microbiology. Aim 1 will elucidate the biofilm functionality of CdrA and its processed forms within P. aeruginosa biofilms including those found in chronic infections. Aim 2 will examine the ability of CdrA to integrate host material into biofilms and determine if these host factor- integrated biofilms are more protected against antimicrobials and host immune responses. These aims are expected to transform the established view of biofilm matrices as static structures that are formed by only self- produced biomolecules. This improved understanding will advance biofilm microbiology and aid the creation of effective treatments for chronic infections. This proposal includes a career development plan to complement Dr. Reichhardt’s prior experience so that she can successfully transition to an independent research faculty position. Dr. Reichhardt has assembled a multidisciplinary mentorship committee to help her achieve her scientific and career development goals. Professor Parsek is an ideal mentor for Dr. Reichhardt since he is internationally recognized as a leader in biofilm microbiology, and he has a strong track record producing successful independent academic scientists, including several with multidisciplinary backgrounds. The proposed research is distinct from that of Professor Parsek, and the results of this project will transition with Dr. Reichhardt to her future independent research program. Additionally, results generated from the proposed research aims are expected to help Dr. Reichhardt successfully compete for R01 funding.

项目概要/摘要 称为生物膜的微生物群落是慢性感染的标志，铜绿假单胞菌是一种模型。 用于生物膜研究，也是引起生物膜感染（包括烧伤、伤口、尿道感染）的病原体 囊性纤维化 (CF) 患者的导管、隐形眼镜和气道中都含有生物膜微生物。 网状细胞外基质，帮助细菌逃避宿主防御并抵御外部攻击 例如抗菌治疗，有必要更好地了解生物膜基质组装。 预防和治疗生物膜相关感染是本申请和候选者的长期目标， Reichhardt 博士将建立一个独立的研究项目，重点研究天然和功能性的影响 为了实现这一目标，Reichhardt 博士的近期职业目标是 使用拟议的研究作为工作申请的基础，获得独立的教职职位。 本申请的总体研究目标是研究基质相互作用的灵活性和控制 关键的铜绿假单胞菌蛋白 CdrA 基于初步数据，假设是生物膜功能。 CdrA 的数量可以通过酶处理和与宿主因子的结合来扩展，从而影响生物膜的稳定性。 为了检验这一假设，提出了两个具体目标，并将使用 Reichhardt 博士独特的方法进行研究 生物物理化学和微生物学的多学科培训目标 1 将阐明生物膜的功能。 铜绿假单胞菌生物膜中的 CdrA 及其加工形式，包括慢性感染中发现的那些。 将检查 CdrA 将宿主材料整合到生物膜中的能力，并确定这些宿主因素是否- 整合的生物膜可以更好地抵御抗菌药物和宿主免疫反应。 预计将改变生物膜基质作为仅由自身形成的静态结构的既定观点 这种更好的理解将促进生物膜微生物学的发展，并有助于创造生物分子。 该提案包括对慢性感染的有效治疗方法，以补充博士的职业发展计划。 Reichhardt 之前的经验使她能够成功过渡到独立研究教员职位。 Reichhardt 博士组建了一个多学科指导委员会来帮助她实现科学和 Parsek 教授是 Reichhardt 博士的理想导师，因为他是国际化的。 他被公认为生物膜微生物学领域的领导者，并且在生产成功方面拥有良好的记录 独立学术科学家，其中包括几位具有多学科背景的科学家。 与 Parsek 教授的研究不同，该项目的结果将与 Reichhardt 博士一起转移给她 此外，拟议研究目标产生的结果是 预计将帮助 Reichhardt 博士成功竞争 R01 资金。