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.

项目摘要/摘要 该建议描述了一项严格的培训计划，导致安德鲁·王博士的职业发展为 独立的医师科学家。 首席研究员是一名医师科学家，拥有免疫生物学博士学位，最近完成了临床 风湿病学奖学金培训。他的职业目标是成为研究组织的独立调查员 对炎症的耐受性。他建议通过密集地扩大他在炎症生物学的培训 在Ruslan Medzhitov博士的指导下培训研究经验，他是一位先驱和世界领导者 无与伦比的智力和技术洞察力，可以解决复杂的炎症生物学。此外 Medzhitov博士实验室的知识修饰和动手培训，这是一系列严格的教学 课程工作和精心选择的咨询委员会由医师科学家组成 与该项目相关的专业知识，并在成功培养医师科学家方面拥有丰富的经验 职业将使他具备成为成功的独立调查员的必要技能。 该提案的研究目标是了解葡萄糖代谢如何调节组织耐受性 不同类型的炎症。该提案的初步数据表明，补充营养 在细菌败血症的李斯特菌模型中增强杀伤力，同时预防杀伤性 病毒败血症。确定食物的致病成分是葡萄糖。致命性独立于 全身炎症或病原体负担的程度。在细菌的无菌模型中概括了发现 和病毒败血症，其中葡萄糖代谢的治疗性阻断了二脱氧葡萄糖 细菌败血症的脂多糖模型可保护死亡率，而治疗性阻塞 病毒败血症的多I：C模型中的葡萄糖代谢导致死亡率增强，与程度无关 炎症。我们假设不同类型的炎症在 为了协调组织保护所必需的细胞保护反应的适当激活 炎症损害。该建议研究了酮生物学在介导细菌保护中的作用 炎症和干扰素α介导的葡萄糖依赖性展开蛋白反应的作用 病毒炎症。 该建议是安德鲁·王（Andrew Wang）博士成为炎症专家的训练工具， 代谢控制和对炎症的组织反应，以便他可以将自己的专业知识应用于领域 风湿病。