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: 8416557
• 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/8416557
• 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. PUBLIC HEALTH RELEVANCE: Hospital-acquired infections are the sixth leading cause of death in the United States and often result in non-healing wounds. A recent trend regards hospital-acquired infections and pressure ulcers as the result of conditions in (and thus the burden of) healthcare facilities, causing the Centers for Medicare and Medicaid Services to cease paying hospitals for these "preventable complications", resulting in a significant shift in the burden of the cost of healthcare ultimately back to the patient, with substantial economic and social ramifications. The studies proposed here have the potential to uncover the mechanisms at the root of the failure of the normal healing process that results in the development of chronic wounds and may provide novel therapeutic paths by manipulation of metabolic pathways that control the relevant immune cell phenotypes. The proposed metabolomic studies on host-pathogen interactions will identify specific metabolite profiles that may be associated with pathogenicity in the chronic wound and could potentially be used in novel diagnostics; therefore, these studies have direct translational potential that may augment the clinical toolbox needed to face the healthcare burden of chronic wounds.

描述(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，解决这一假设，即细菌生物膜在伤口环境中介导针对宿主先天性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。我在天然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，使我能够提出关于免疫细胞-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培训也给了我技术技能，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核磁共振和MS代谢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(如宿主与病原体相互作用)的基本方法。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，以便将全面的代谢组学分析整合到全球系统生物学研究中，研究免疫细胞对细菌生物膜暴露的反应。为了实现这个职业发展奖的目标，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，也有成为有效导师的经验。德拉茨博士有近45名 多年的NIH研究员经验使他成为我团队的高级导师。在获奖过程中，我的目标是获得核磁共振(核磁共振)、质谱学(MS)、电子代谢模型和化学计量学分析方面的专业知识，与Copi？博士、Bothner博士和Carlson博士密切合作，他们都是各自科学学科的专家。除了获得进行拟议的代谢组学研究所需的技术技能外，我还将寻求专业发展。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指导，参与负责任的研究行为培训，以及通过参与会议、出版以及赠款和手稿的同行审查过程参与更大的科学界。蒙大拿州立大学(MSU)为这项培训提供了极佳的环境，拥有在过去几年中为开发最先进的代谢组学/系统生物学研究中心而购买的设施和设备，包括获得核磁共振、MS和生物信息学方面的核心设施经理的专业知识。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。这一职业发展计划的直接目标不仅是获得上述技术专长，而且还将这些培训应用于建立我自己的研究计划。我的初步工作让我产生了这样的假设，即先天免疫细胞和细菌生物膜之间的界面会产生不同的代谢谱，可以用于治疗，或许也可以用于诊断。为了评估这一假说的有效性，我建议确立机会型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，证明在体外暴露于铜绿假单胞菌生物膜会导致先天免疫细胞的代谢偏离，作为表型向炎症转变的一部分，并建立在体外宿主-病原体慢性创伤模型中引入乳铁蛋白导致病原体的代谢饥饿，同时将固有免疫细胞转移到驻留的巨噬细胞表型，从而更有效地解决炎症，使伤口进展到消退。本文提出的研究有可能揭示导致慢性创面发展的偏离正常愈合过程的根源机制，并将提供分子知识，这些知识可能长期用于通过操纵控制免疫细胞表型的代谢途径来开发新的治疗途径。 公共卫生相关性：在美国，医院获得性感染是第六大死亡原因，往往导致无法愈合的伤口。最近的一种趋势认为，医院获得性感染和压疮是医疗设施状况(因此是医疗机构的负担)的结果，导致医疗保险和医疗补助服务中心停止向医院支付这些“可预防的并发症”，导致医疗成本的负担最终显著转移到患者身上，产生了重大的经济和社会后果。本文提出的研究有可能揭示导致慢性创面发展的正常愈合过程失败的根本机制，并可能通过操纵控制相关免疫细胞表型的代谢途径提供新的治疗途径。拟议的关于宿主-病原体相互作用的代谢组学研究将确定可能与慢性伤口的致病性相关的特定代谢物图谱，并可能被用于新的诊断；因此，这些研究具有直接的翻译潜力，可能增加面对慢性伤口的医疗负担所需的临床工具箱。