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: 9899233
• 负责人: Tuyet-Hang Nghiem-Rao
• 金额: $ 17.78万
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899233
• 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; Multi-site clinical study; 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; hepatocyte injury; 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.

项目概要/摘要 该提案的目标是提供一条作为临床转化研究者独立的途径 早产儿和危重婴儿的营养。全肠外营养（TPN）是最常见的一种 新生儿重症监护病房 (NICU) 提供的治疗。然而，TPN 的安全性显着 受到肠外营养相关肝病（PNALD）风险的限制。大豆脂质中的植物甾醇 TPN 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 患有 PNALD 的婴儿的甾醇明显升高，并且年龄影响甾醇代谢和表达 重要的肝脏甾醇调节基因。我们对 PNALD 的理解存在两个关键的知识空白： 1) 婴儿在长期接触大豆脂质期间管理外源植物甾醇的能力；2) 新生儿易受 PNALD 影响的机制。我的首要职业目标是关闭 成为甾醇代谢和 PNALD 方面的专家，以开发和应用新型药物，从而弥补知识差距 提高婴儿 TPN 安全性的干预措施。我的职业发展计划逻辑上延伸了我之前的 新生儿学和临床研究培训。我将获得转化研究方面的知识和培训， 甾醇调节途径、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咨询委员会 多中心转化研究、甾醇代谢、干细胞技术和肝脏方面的专业知识 发展将指引我。我假设植物甾醇浓度与风险增加相关 PNALD 的发生受到胎龄和关键甾醇调节基因表达失败的影响。我会 通过两个具体目标来检验这一假设。目标 1 寻求确定系列植物甾醇的动力学 长期摄入大豆脂质的婴儿体内的积累及其与胆汁淤积的关系。这将完成 使用前瞻性、多中心临床研究来测量连续植物甾醇和胆固醇水平 大豆脂质治疗期间至少 2 周的婴儿血液。目标 2 寻求鉴定基因表达和脂质 在不同发育阶段暴露于植物甾醇的患者来源肝细胞中的积累。这 将使用源自匹配研究参与者 iPSC 的未成熟和成熟肝细胞进行评估 有和没有 PNALD。在此奖项期间获得的成果和专业知识将使我能够建立一个 独立的临床转化研究计划，最终提高危重病患者的营养安全 新生儿。