Regulation of Metabolic Programs for Host Tolerance to Inflammation

调节宿主对炎症的耐受性的代谢程序

• 批准号: 9224559
• 负责人: Andrew Wang
• 金额: $ 14.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224559
• 关键词: Adipocytes; Advisory Committees; Animals; Anorexia; Apoptosis; Attenuated; Autoimmune Diseases; Bacterial Model; Biology; Cell Death; Cells; Cessation of life; Clinical; Complex; Critical Care; Critical Illness; Data; Disease; Doctor of Philosophy; Fellowship; Food; Fostering; Functional disorder; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Grooming; HDAC4 gene; Immunity; Immunobiology; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Injury; Interferon-alpha; Interruption; Intervention; Ketone Bodies; Ketones; Lead; Lipolysis; Lipopolysaccharides; Listeria; Mediating; Mentorship; Metabolic; Metabolic Control; Metabolism; Modeling; Morbidity - disease rate; Mus; Nicotinic Acids; Organ; Organ failure; Outcome; PPAR alpha; Pathway interactions; Pharmacology; Physicians; Physiological Processes; Poly I-C; Principal Investigator; Proteins; Regulation; Research; Research Personnel; Research Training; Rheumatism; Rheumatology; Role; Scientist; Sepsis; Septic Shock; Series; Signal Transduction; Sterility; Stress; Supplementation; Syndrome; System; Testing; Therapeutic; Tissues; Training; Training Programs; Viral; Viremia; antimicrobial; career; career development; deprivation; experience; experimental study; flu; glucose metabolism; improved; in vivo; inhibitor/antagonist; insight; interferon alpha receptor; ketogenesis; ketogentic; man; mortality; nutrition; nutritional supplementation; oxidation; pathogen; prevent; programs; receptor; response; skills; transcription factor; transcription factor CHOP

PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program leading to the career development of Dr. Andrew Wang as an independent physician scientist. The principal investigator is a physician scientist with a PhD in Immunobiology who recently completed clinical fellowship training in Rheumatology. His career goal is to become an independent investigator studying tissue tolerance to inflammation. He proposes to expand his training in inflammation biology through an intensive training research experience under the mentorship of Dr. Ruslan Medzhitov, a pioneer and world leader with unparalleled intellectual and technical insight into tackling the complex biology of inflammation. In addition to intellectual grooming and hands-on training in Dr. Medzhitov's lab, a proposed rigorous series of didactic coursework and a carefully selected advisory committee comprised of physician-scientists with a broad range of expertise related to this project and with extensive experience in successfully fostering physician-scientist careers will equip him with the necessary skills to become a successful independent investigator. The research objective of this proposal is to understand how glucose metabolism regulates tissue tolerance to different types of inflammation. Preliminary data for this proposal reveals that nutritional supplementation enhances lethality in the Listeria model of bacterial sepsis while it protects against lethality in the flu model of viral sepsis. The causative component of food was determined to be glucose. Lethality was independent of the extent of systemic inflammation or pathogen burden. Findings were recapitulated in sterile models of bacterial and viral sepsis where therapeutic blockade of glucose metabolism with 2-deoxy glucose in the lipopolysaccharide model of bacterial sepsis lead to protection from mortality while therapeutic blockade of glucose metabolism in a Poly I:C model of viral sepsis lead to enhanced mortality, independent of the degree of inflammation. We hypothesized that different types of inflammation induced different metabolic states in order to coordinate appropriate activation of cytoprotective responses necessary for tissue protection from inflammatory damage. This proposal examines the role of ketone biology in mediating protection to bacterial inflammation and the role of the interferon alpha-mediated glucose-dependent unfolded protein response in viral inflammation. This proposal serves as a training vehicle for Dr. Andrew Wang to become an expert in inflammation, metabolic control, and tissue response to inflammation so that he can apply his expertise to the field of rheumatic diseases.

项目总结/摘要 该提案描述了一个严格的培训计划，导致Andrew Wang博士的职业发展， 独立的医学科学家 主要研究者是一位拥有免疫生物学博士学位的内科科学家，最近完成了临床研究 流变学的奖学金培训。他的职业目标是成为一名研究组织的独立调查员 对炎症的耐受性。他建议通过一个密集的课程来扩大他在炎症生物学方面的训练。 在Ruslan Medzhitov博士的指导下，培训研究经验，Ruslan Medzhitov博士是一位先驱和世界领导者， 在解决炎症的复杂生物学方面具有无与伦比的智力和技术洞察力。除了 在Medzhitov博士的实验室里进行智力培养和实践培训， 课程和一个精心挑选的咨询委员会组成的医生，科学家与广泛的 拥有与该项目相关的专业知识，并在成功培养医生科学家方面拥有丰富的经验 职业生涯将使他具备成为一名成功的独立调查员所需的技能。 这项研究的目的是了解葡萄糖代谢如何调节组织对葡萄糖的耐受性。 不同类型的炎症。该提案的初步数据显示， 增强李斯特菌细菌性脓毒症模型的致死性，而它保护免受流感模型的致死性， 病毒性败血症食物的致病成分被确定为葡萄糖。致死率与 全身炎症或病原体负荷的程度。在无菌细菌模型中， 和病毒性脓毒症，其中用2-脱氧葡萄糖治疗性阻断葡萄糖代谢， 细菌性脓毒症脂多糖模型导致保护免于死亡， 在病毒性脓毒症的Poly I：C模型中，葡萄糖代谢导致死亡率增加，与程度无关 炎症。我们假设，不同类型的炎症诱导不同的代谢状态， 为了协调组织保护所必需的细胞保护反应的适当激活， 炎性损伤该提案研究了酮生物学在介导对细菌的保护中的作用， 炎症和干扰素α介导的葡萄糖依赖性未折叠蛋白应答在 病毒性炎症 这项建议是安德鲁·王博士成为炎症专家的培训工具， 代谢控制和组织对炎症的反应，以便他可以将他的专业知识应用于 风湿性疾病