Role of Prematurity and Sterol Metabolism in Parenteral Nutrition-Associated Liver Disease

早产和甾醇代谢在肠外营养相关肝病中的作用

• 批准号: 9514990
• 负责人: Tuyet-Hang Nghiem-Rao
• 金额: $ 17.77万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9514990
• 关键词: Adult; Advisory Committees; Affect; Age; Alcohols; Animals; Award; Bile Acids; Biological Models; Blood; CYP8B1 gene; Cell membrane; Center for Translational Science Activities; Cessation of life; Child; Cholestasis; Cholesterol; Clinical; Clinical Research; Critical Illness; Data; Development; Development Plans; Disease susceptibility; Emulsions; Excretory function; Exposure to; Expression Profiling; Failure; Gene Expression; Gene Mutation; Genes; Genetic Predisposition to Disease; Gestational Age; Goals; Hepatic; Hepatocyte; Human; Human Development; Impairment; Infant; Injury; Intervention; Kinetics; Knowledge; Laboratories; Lead; Lipids; Liver; Liver diseases; Mass Fragmentography; Measures; Mentors; Metabolic Pathway; Metabolism; Molecular; Neonatal Intensive Care Units; Neonatology; Newborn Infant; Nuclear Receptors; Oils; Parenteral Nutrition; Participant; Pathogenesis; Pathway interactions; Patients; Phytosterols; Plant Components; Plasma; Positioning Attribute; Pregnancy; Premature Infant; Prospective cohort study; Proteins; Research; Research Activity; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Safety; Steroids; Sterols; Techniques; Testing; Time; Total Parenteral Nutrition; Training; Training Activity; Translational Research; United States; United States National Institutes of Health; Universities; Wisconsin; Work; base; career; career development; clinically relevant; critically ill newborn; experience; hypercholesterolemia; improved; in vitro Model; induced pluripotent stem cell; infancy; innovation; insight; liver development; liver injury; mathematical model; medical schools; neonate; next generation; novel; nutrition; premature; prospective; recruit; response; soy; stem cell technology; technology development; transcriptome sequencing; translational research program; translational scientist; translational study

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to provide a pathway to independence as a clinical-translational investigator in the nutrition of premature and critically ill infants. Total parenteral nutrition (TPN) is one of the most common therapies provided in the neonatal intensive care unit (NICU). However, the safety of TPN is significantly limited by the risk for parenteral nutrition-associated liver disease (PNALD). Plant sterols in the soy-based lipid component of TPN are believed to be a contributing factor to liver injury. My prior studies showed that plant sterols are markedly elevated in infants with PNALD and that age impacts sterol metabolism and expression of important hepatic sterol-regulating genes. Two critical gaps in knowledge exist in our understanding of PNALD: 1) the ability of infants to manage exogenous plant sterols during prolonged soy lipid exposure and 2) the mechanism that underlies the vulnerability of neonates to PNALD. My overarching career goal is to close the knowledge gap by becoming an expert in sterol metabolism and PNALD in order to develop and apply novel interventions to improve the safety of TPN in infants. My career development plan logically extends my prior training in neonatology and clinical research. I will attain knowledge and training in translational research, sterol-regulating pathways, iPSC-derived hepatocytes, and liver development. Experienced mentors and a scientific advisory committee at the Medical College of Wisconsin, University of Cincinnati, and the NIH with expertise in multi-center translational research, sterol metabolism, stem cell technologies, and liver development will guide me. I hypothesize that plant sterol concentrations associated with increased risk for PNALD are influenced by gestational age and failure to express key sterol-regulating genes. I will test this hypothesis through two specific aims. Aim 1 seeks to determine the kinetics of serial plant sterol accumulation and their association with cholestasis in infants receiving prolonged soy lipids. This will be done using a prospective, multicenter clinical study to measure serial plant sterol and cholesterol levels in the blood of infants during soy lipid therapy of at least 2 weeks. Aim 2 seeks to identify gene expression and lipid accumulation in patient-derived hepatocytes exposed to plant sterols at different developmental stages. This will be assessed using immature and mature hepatocytes derived from the iPSC of matched study participants with and without PNALD. Results and expertise acquired during this award will position me to establish an independent, clinical-translational research program to ultimately improve the safety of nutrition in critically ill neonates.

项目摘要/摘要 这项建议的目标是提供一条独立的途径，作为一名临床翻译研究员在 早产儿和危重婴儿的营养。全肠外营养(TPN)是最常见的 新生儿重症监护病房(NICU)提供的治疗。然而，TPN的安全性是显著的 受非肠外营养相关性肝病(PNALD)风险的限制。大豆基脂中的植物甾醇 TPN的成分被认为是导致肝损伤的一个因素。我之前的研究表明，植物 PNALD患儿血中固醇水平显著升高，年龄影响血中的固醇代谢和 重要的肝脏类固醇调节基因。在我们对PNALD的理解中，存在两个关键的知识差距： 1)婴儿在长时间接触大豆脂期间管理外源植物类固醇的能力和2) 新生儿易患PNALD的机制。我的首要职业目标是结束 成为固醇代谢和PNALD专家的知识差距，以开发和应用新技术 提高婴幼儿TPN安全性的干预措施。我的职业发展计划合乎逻辑地扩展了我的职业生涯 新生儿学和临床研究方面的培训。我将获得翻译研究方面的知识和培训， 类固醇调节途径、IPSC衍生的肝细胞和肝脏发育。经验丰富的导师和 威斯康星医学院、辛辛那提大学和美国国立卫生研究院的科学顾问委员会 在多中心翻译研究、类固醇代谢、干细胞技术和肝脏方面的专业知识 发展会指引我的方向。我假设植物类固醇浓度与增加风险有关 PNALD的发生受胎龄和未能表达关键的类固醇调节基因的影响。这就做 通过两个具体目标来检验这一假设。目的1测定系列植物甾醇的动力学 长期服用大豆脂类的婴儿的蓄积及其与胆汁淤积的关系。这件事会做到的 使用一项前瞻性多中心临床研究来测量一系列植物类固醇和胆固醇水平 在至少2周的大豆脂肪治疗期间，婴儿的血液。目标2试图确定基因表达和脂类 患者来源的肝细胞在不同发育阶段暴露于植物甾醇中的蓄积。这 将使用来自匹配研究参与者的IPSC的未成熟和成熟肝细胞进行评估 使用和不使用PNALD。在此奖项期间获得的结果和专业知识将使我能够建立 独立的临床-转译研究计划，最终提高危重患者的营养安全性 新生儿。