Metabolomic Analysis as a Tool to Understanding the Use of Novel Therapeutics in

代谢组学分析作为了解新疗法在疾病中的应用的工具

• 批准号: 8721452
• 负责人: Mary Cloud Bosworth Ammons
• 金额: $ 9.87万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721452
• 关键词: Address; Award; Back; Bacteria; Bioinformatics; Biology; Cause of Death; Cells; Cellular biology; Chronic; Clinical; Communities; Computer Simulation; Core Facility; Data; Decubitus ulcer; Development; Development Plans; Diagnostic; Discipline; Economics; Engineering; Environment; Equipment; Exposure to; Face; Failure; Goals; Grant; Growth; Healed; Health Care Costs; Health care facility; Healthcare; Hospitals; Human; Immune; Immunology; In Vitro; Inflammation; Iron; Iron Chelating Agents; Journals; K-Series Research Career Programs; Knowledge; Lactoferrin; Lead; Manuscripts; Mass Spectrum Analysis; Mediating; Mediation; Medical; Mentors; Mentorship; Metabolic; Metabolic Pathway; Methods; Microbial Biofilms; Modeling; Molecular; Montana; Nosocomial Infections; Nuclear Magnetic Resonance; Pathogenicity; Patients; Pattern; Peer Review; Phenotype; Plant Roots; Process; Proteins; Pseudomonas aeruginosa; Publications; Relative (related person); Research; Research Personnel; Research Training; Resolution; Starvation; Systems Biology; Technical Expertise; Therapeutic; Training; United States; United States Centers for Medicare and Medicaid Services; United States National Institutes of Health; Universities; Variant; Work; Wound Healing; analytical tool; base; career; career development; deprivation; experience; graduate student; healing; innovation; insight; interest; lectures; macrophage; metabolomics; novel diagnostics; novel therapeutics; pathogen; programs; response; responsible research conduct; skills; social; symposium; tool; trend; wound

DESCRIPTION (provided by applicant): My long-term career goal is to establish an independent research career addressing the hypothesis that bacterial biofilms mediate specific pathological effects against host innate immune cells within the wound environment which result in deviations from the normal wound healing process and lead to wound chronicity. My background in innate immunology and medical biofilms provides me with unique expertise enabling me to ask innovative and fundamental questions regarding immune cell-bacteria biofilm interactions. My research training as a graduate student in molecular methods and cell biology has also given me technical skills that will enable me to apply such tools for systems biology analysis of the chronic wound models; at present, I aim to complete my training by gaining expertise in NMR and MS metabolomic analysis, an essential approach to solving systems biology problems such as host- pathogen interactions. My goal with this career development plan is to develop the expertise and master the analytical tools necessary to integrate comprehensive metabolomics analyses into a global systems biology study of immune cell responses to bacterial biofilm exposure. To address my objectives for this career development award, I have assembled a mentorship team with both the expertise to train me in the technical skils of interest and the experience to be effective mentors. Dr. Dratz has nearly 45 years of experience as a NIH supported researcher making him an excellent choice as Senior Mentor of my team. In the course of this award, my objective is to acquire expertise in nuclear magnetic resonance (NMR), mass spectrometry (MS), in silico metabolic modeling, and chemometric analysis working closely with Drs. Copi¿, Bothner, and Carlson all experts in their respective scientific disciplines. In adition to acquiring technical skils necessary to undertake te proposed metabolomics studies, I will seek out professional development. To that end, my career development plan includes participation in educational opportunities such as guest lecturing and the mentorship of a graduate student, participation in training for the Responsible Conduct of Research, and engagement in the larger scientific community through participation in conferences, publication, and the peer-review process of grants and manuscripts. Montana State University (MSU) provides an excellent environment for this training with facilities and equipment that has been acquired within the last few years to develop a state-of-the-art Metabolomics/Systems Biology Research Center, including access to the expertise of core facility managers in NMR, MS, and bioinformatics. In addition, opportunities for intellectual stimulation abound including the Systems Biology Journal Club and cross-disciplinary research. The immediate objective of this career development plan is not only to acquire the technical expertise outlined above, but also to apply that training to the establishment of my own research program. My preliminary work led me to the hypothesis that the interface between innate immune cells and bacterial biofilms result in distinct metabolic profiles that can be manipulated for therapeutic treatment and perhaps can also be used for diagnostics. To assess the validity of this hypothesis, I propose to establish that the biofilm mode of growth of the opportunistic chronic wound pathogen P. aeruginosa results in distinct metabolic patterns and that the biofilms are especially sensitive to iron deprivation by the immune molecule lactoferrin, document that exposure to P. aeruginosa biofilms in vitro results in a metabolic deviation in innate immune cells as part of a phenotypic shift towards inflammation, and establish that introduction of lactoferrin to the in vitro host-pathogen chronic wound model results in metabolic starvation of the pathogen while shifting the innate immune cells toward a resident macrophage phenotype that more efectively resolves inflammation allowing the wound to progress to resolution. The studies proposed here have the potential to uncover mechanisms at the root of deviations from the normal healing process that result in the development of chronic wounds, and will provide molecular knowledge that may be used in the long term to develop novel therapeutic paths by the manipulation of metabolic pathways that control immune cell phenotype.

描述（由申请人提供）：我的长期职业目标是建立一个独立的研究生涯，解决以下假设：细菌生物膜介导伤口环境中针对宿主先天免疫细胞的特定病理效应，导致偏离正常伤口愈合过程并导致伤口慢性化。我在先天免疫学和医学生物膜方面的背景为我提供了独特的专业知识，使我能够提出有关免疫细胞-细菌生物膜相互作用的创新和基本问题。作为一名研究生，我在分子方法和细胞生物学方面的研究训练也给了我技术技能，使我能够将这些工具应用于慢性伤口模型的系统生物学分析;目前，我的目标是通过获得NMR和MS代谢组学分析方面的专业知识来完成我的培训，这是解决系统生物学问题（如宿主-病原体相互作用）的重要方法。我这个职业发展计划的目标是发展专业知识并掌握必要的分析工具，将全面的代谢组学分析整合到细菌生物膜暴露的免疫细胞反应的全球系统生物学研究中。 为了实现我的职业发展目标，我组建了一个导师团队，他们既有培训我感兴趣的技术技能的专业知识，又有成为有效导师的经验。Dratz博士有将近45个 多年的经验，作为一个国家卫生研究所支持的研究人员，使他成为一个很好的选择，作为我的团队的高级导师。在这个奖项的过程中，我的目标是获得专业知识，在核磁共振（NMR），质谱（MS），在硅代谢建模，和化学计量学分析与博士密切合作。为了获得进行代谢组学研究所需的技术技能，我将寻求专业发展。为此，我的职业发展计划包括参与教育机会，如客座演讲和研究生的导师，参与研究的负责任行为的培训，并通过参与会议，出版和同行评审过程参与更大的科学界的赠款和手稿。蒙大拿州州立大学（MSU）为这种培训提供了一个良好的环境，其设施和设备在过去几年中已经获得，以开发最先进的代谢组学/系统生物学研究中心，包括获得NMR，MS和生物信息学核心设施管理人员的专业知识。此外，智力刺激的机会比比皆是，包括系统生物学杂志俱乐部和跨学科研究。 该职业发展计划的直接目标不仅是获得上述技术专业知识，而且是将该培训应用于建立我自己的研究计划。我的初步工作使我提出了一个假设，即先天免疫细胞和细菌生物膜之间的界面导致了不同的代谢谱，这些代谢谱可以用于治疗性治疗，也许也可以用于诊断。为了评估这一假设的有效性，我建议建立机会性慢性伤口病原体铜绿假单胞菌的生物膜生长模式导致不同的代谢模式，并且生物膜对免疫分子乳铁蛋白的铁剥夺特别敏感，文献表明，在体外暴露于铜绿假单胞菌生物膜导致先天免疫细胞的代谢偏离，作为表型向炎症，并建立将乳铁蛋白引入体外宿主-病原体慢性创伤模型，导致病原体代谢饥饿，同时使先天免疫细胞向更有效地解决炎症的驻留巨噬细胞表型转变，从而允许创伤进展到解决。本文提出的研究有可能揭示导致慢性伤口发展的正常愈合过程偏离的根本机制，并将提供可长期用于通过控制免疫细胞表型的代谢途径来开发新的治疗途径的分子知识。