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

基本信息

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
项目类别：
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

项目摘要

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.