Role of Lipid Metabolism in Hepatic Ischemia Reperfusion Injury in Steatotic Livers

脂质代谢在脂肪肝缺血再灌注损伤中的作用

• 批准号: 10664736
• 负责人: Kim Hung Ho Liss
• 金额: $ 16.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664736
• 关键词: Address; Adipocytes; Adipose tissue; Anti-Inflammatory Agents; Attenuated; Award; Benign; Bioinformatics; Biological Markers; Bone Marrow; Caring; Cell Death; Chemicals; Chemistry; Childhood; Coculture Techniques; Communities; Data; Development Plans; Developmental Biology; Drug Targeting; Environment; Experimental Models; Extrahepatic; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fellowship; Fibrosis; Functional disorder; Funding; Gastroenterology; Genomics; Goals; Hepatic; Hepatic Tissue; Hepatocyte; Hepatology; High Fat Diet; Homeostasis; Hydrolysis; Hypoxia; Immunology; In Vitro; Incubators; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Intervention; Knock-out; Knowledge; Knowledge acquisition; Kupffer Cells; Laboratories; Learning; Lecithin; Lipase; Lipid Synthesis Pathway; Lipids; Lipolysis; Liver; Liver Failure; Macrophage; Mediating; Mediator; Medicine; Mentors; Metabolic Pathway; Metabolism; Mus; Natural regeneration; Nonesterified Fatty Acids; Operative Surgical Procedures; Organ; Organ Donations; Organ Donor; Outcome; Patient-Focused Outcomes; Pediatrics; Persons; Phenotype; Phospholipids; Physicians; Plasma; Predisposition; Prevalence; Process; Recording of previous events; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Training; Resources; Role; Scientist; Secondary to; Structure; Technical Expertise; Testing; Therapeutic Intervention; Training; Transplantation; Triglycerides; United States National Institutes of Health; Universities; Waiting Lists; Washington; Wild Type Mouse; Work; career; career development; cell injury; cytotoxic; drug development; graft function; improved; inhibitor; insight; interest; intrahepatic; knock-down; lipid metabolism; lipidome; lipidomics; liver injury; liver ischemia; liver transplantation; medical schools; metabolomics; mortality; multiple omics; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; nutrition; prevent; recruit; response; single nucleus RNA-sequencing; skills; theories; tissue repair; transcriptome sequencing

PROJECT SUMMARY This proposal describes a 3-year plan to prepare Dr. Kim Liss, MD, for independence as a physician scientist, studying the role of lipid metabolism in ischemia reperfusion injury (IRI) in steatotic livers. During her Pediatric Gastroenterology, Hepatology & Nutrition fellowship at Washington University School of Medicine, Dr. Liss undertook research training in Dr. Brian Finck’s laboratory, where she demonstrated that steatosis significantly worsens hepatic IRI in an experimental model. She also found that manipulation of a single lipid synthesis pathway has far-reaching effects on inflammation, cell death, and regeneration in the liver. She extended these findings and found alterations in multiple lipid metabolic pathways and macrophage subpopulations in response to IRI. These findings serve as the basis for her proposal. Washington University School of Medicine is an outstanding environment for Dr. Liss to further her research training, with its longstanding history of NIH-funded research, breadth and depth of resources, and, most importantly, commitment to launching young investigators. There is constant crosstalk between departments and research groups. Dr. Liss’ mentoring committee and collaborators have expertise spanning Pediatrics, Medicine, Surgery, Chemistry, Immunology, and Developmental Biology. Dr. Finck is a well-suited primary mentor because he is a leader in the field of intermediary metabolism and has an established record of training young scientists during their transition to independence. Furthermore, the Finck laboratory is a hub of intellectual energy with its trainees working on a broad range of inter-related projects. Dr. Liss will have abundant opportunities to present her work within Washington University and the wider scientific community. Her mentor team has complementary skills, and her Division and Department are highly supportive of her goals. She will take graduate classes to enhance her knowledge of metabolomics, genomics, and bioinformatics, and develop technical skills with her mentors and collaborators. At award conclusion, she will have acquired the knowledge and skills to become an independent physician scientist with special expertise in hepatic steatosis relevant to liver transplant care. In parallel to pursuing her structured career development plans, Dr. Liss will accomplish her proposed Aims: 1) determine how adipose tissue lipolysis interacts with the liver in the context of hepatic IRI, and 2) define changes to the hepatic lipidome that determine the macrophage landscape in hepatic IRI. Using advanced multi-omics approaches, Dr. Liss strives to develop an integrated understanding of the factors that contribute to IRI and recovery. Her work will fill the void in our understanding of the pathobiologic mechanisms underlying IRI in steatotic livers, a condition that limits organ use, and threatens graft function. The efforts described in this proposal will prompt novel interventions to increase donor organ availability, decrease waitlist mortality, improve patient outcomes, and, in the process, serve as a springboard for Dr. Liss’ research career.

项目概要 该提案描述了一项三年计划，旨在帮助医学博士 Kim Liss 做好独立成为一名医师科学家的准备， 研究脂质代谢在脂肪肝缺血再灌注损伤（IRI）中的作用。在她儿科期间 华盛顿大学医学院胃肠病学、肝病学和营养学奖学金，Liss 博士 在 Brian Finck 博士的实验室接受研究培训，她证明脂肪变性显着 在实验模型中使肝脏 IRI 恶化。她还发现，操纵单一脂质合成 该途径对肝脏的炎症、细胞死亡和再生具有深远的影响。她扩展了这些 研究结果发现多种脂质代谢途径和巨噬细胞亚群发生改变 对 IRI 的回应。这些发现是她提案的基础。 华盛顿大学医学院为 Liss 博士提供了进一步发展的良好环境 研究培训，具有 NIH 资助研究的悠久历史、资源的广度和深度，以及， 最重要的是，致力于培养年轻的研究人员。之间存在持续的串扰 部门和研究小组。利斯博士的指导委员会和合作者拥有跨领域的专业知识 儿科、医学、外科、化学、免疫学和发育生物学。芬克博士非常适合 主要导师，因为他是中间代谢领域的领导者，并且在 在年轻科学家向独立过渡期间对其进行培训。此外，芬克实验室是 智力能量及其受训人员从事广泛的相互关联的项目。利斯博士将有 在华盛顿大学和更广泛的科学界展示她的工作的大量机会。 她的导师团队技能互补，她的部门和部门都非常支持她 目标。她将参加研究生课程，以增强她在代谢组学、基因组学和 生物信息学，并与她的导师和合作者一起发展技术技能。在颁奖结束时，她将 已获得成为一名独立医师科学家的知识和技能，具有以下方面的特殊专业知识 与肝移植护理相关的肝脂肪变性。 在追求结构化的职业发展计划的同时，利斯博士将完成她提出的建议 目的：1) 确定脂肪组织脂解作用在肝脏 IRI 情况下如何与肝脏相互作用，2) 定义肝脏脂质组的变化，从而决定肝脏 IRI 中的巨噬细胞景观。使用 凭借先进的多组学方法，Liss 博士致力于对影响因素的综合理解 有助于 IRI 和康复。她的工作将填补我们对病理生物学机制理解的空白 脂肪肝中潜在的IRI是一种限制器官使用并威胁移植物功能的疾病。所做的努力 该提案中描述的将促使采取新的干预措施，以增加捐赠器官的可用性，减少候补名单 死亡率、改善患者治疗结果，并在此过程中成为 Liss 博士研究生涯的跳板。