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（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的假设，从而导致正常伤口愈合过程的偏差和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。还为我提供了技术技能，使我能够应用此类工具对慢性伤口模型进行系统生物学分析，我的目标是通过获得 NMR 和 MS 代谢组分析的专业知识来完成我的培训，这是解决系统生物学问题的重要方法；我的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免疫细胞对细菌生物膜暴露反应的全球系统生物学研究中，以实现我的目标。这个职业发展奖，我已经集结了导师Dratz 博士拥有近 45 名团队，他们既具有培训我感兴趣的技术技能的专业知识，又具有成为有效导师的经验。 多年作为 NIH 支持的研究人员的经验使他成为我团队的高级导师的绝佳选择。在获得该奖项的过程中，我的目标是获得核磁共振 (NMR)、质谱 (MS) 和计算机代谢方面的专业知识。与 Copi 博士密切合作进行建模和化学计量分析。 、博思纳和卡尔森都是各自科学学科的专家，除了获得进行代谢组学研究所需的技术技能之外，我还将寻求专业发展，为此，我的职业发展计划包括参与客座等教育机会。研究生的讲座和指导，参与负责任的研究行为培训，以及通过参加蒙大拿州立大学的会议、出版以及资助和手稿的同行评审过程参与更大的科学界。密歇根州立大学 (MSU) 为此次培训提供了良好的环境，其设施和设备是在过去几年中购置的，旨在发展最先进的代谢组学/系统生物学研究中心，包括获得核心设施管理人员的专业知识此外，还有很多智力刺激的机会，包括系统生物学期刊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，而且是应用。通过培训来建立我的我的初步工作使我提出了这样的假设：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特征，可用于治疗，或许也可用于诊断，以评估该假设的有效性。 ，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，记录暴露于铜绿假单胞菌生物膜在体外导致先天免疫细胞的代谢偏差，作为炎症表型转变的一部分，并确定将乳铁蛋白引入体外宿主-病原体慢性伤口模型会导致病原体的代谢饥饿，同时改变先天免疫细胞针对常驻巨噬细胞表型，更有效地解决炎症，从而使伤口逐渐消退。本文提出的研究有可能揭示导致伤口愈合过程偏离的根源机制。慢性伤口的发展，并将提供可长期使用的分子知识，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。 公共健康相关性：医院获得性感染是美国第六大死亡原因，常常导致伤口无法愈合，最近的趋势认为医院获得性感染和压疮是由于疾病造成的（因此也是负担）。的）医疗机构，导致医疗保险和医疗补助服务中心停止向医院支付这些“可预防并发症”的费用，导致医疗费用负担发生重大转移，最终回到患者身上，从而产生巨大的经济和社会影响这里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失败的根源机制，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致病性相关的特定代谢物谱，并有可能用于新的诊断，因此，这些研究具有直接转化潜力，可能会增强面临的临床工具箱。医疗负担慢性伤口。