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: 10445131
• 负责人: Tuyet-Hang Nghiem-Rao
• 金额: $ 5.93万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445131
• 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; 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.

项目总结/摘要 该提案的目标是提供一条独立的途径，作为临床翻译研究者， 早产儿和重症婴儿的营养。全胃肠外营养（TPN）是最常见的 新生儿重症监护室（NICU）提供的治疗。然而，TPN的安全性显著高于 受肠外营养相关性肝病（PNALD）风险的限制。大豆基脂质中的植物甾醇 认为TPN的组成部分是肝损伤的一个促成因素。我之前的研究表明 PNALD婴儿中甾醇显著升高，年龄影响甾醇代谢和 重要的肝固醇调节基因。在我们对PNALD的理解中存在两个关键的知识差距： 1)婴儿在长时间大豆脂质暴露期间处理外源植物甾醇的能力; 2） 新生儿易患PNALD的潜在机制。我职业生涯的首要目标是 通过成为固醇代谢和PNALD方面的专家，以开发和应用新的 干预措施，以提高婴儿TPN的安全性。我的职业发展计划合理地扩展了我之前的 医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， 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 威斯康星州医学院、辛辛那提大学和NIH的科学咨询委员会， 在多中心转化研究、固醇代谢、干细胞技术和肝脏方面的专业知识 发展将指导我。我假设植物甾醇浓度与风险增加有关， PNALD受胎龄和关键固醇调节基因表达的影响。我会 通过两个具体目标来检验这个假设。目的1是确定系列植物甾醇的动力学 在长期接受大豆脂质的婴儿中，它们的蓄积及其与胆汁淤积的关系。为此将 使用一项前瞻性的多中心临床研究来测量一系列植物甾醇和胆固醇水平， 在至少2周的大豆脂质治疗期间的婴儿血液。目的2旨在确定基因表达和脂质 在不同发育阶段暴露于植物甾醇的患者源性肝细胞中的蓄积。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 有和没有PNALD在此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，以最终提高危重病人的营养安全性 新生儿。

项目成果

NICU management and outcomes of infants with trisomy 21 without major anomalies.

• DOI: 10.1038/s41372-018-0136-5
• 发表时间: 2018-08
• 期刊: Journal of perinatology : official journal of the California Perinatal Association
• 作者: McAndrew S;Acharya K;Nghiem-Rao TH;Leuthner S;Clark R;Lagatta J
• 通讯作者: Lagatta J

Assessing growth of infants with chylothorax receiving fortified skimmed human breast milk.

• DOI: 10.1002/ncp.10887
• 发表时间: 2023-02
• 期刊: Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition

A serum-induced gene signature in hepatocytes is associated with pediatric nonalcoholic fatty liver disease.

肝细胞中血清诱导的基因特征与儿童非酒精性脂肪肝相关。

• DOI: 10.1002/jpn3.12163
• 发表时间: 2024
• 期刊: Journal of pediatric gastroenterology and nutrition
• 影响因子: 2.9
• 作者: HangNghiem-Rao,T;Johnson,JethroS;Pan,Amy;Atkinson,SamanthaN;Behling,Cynthia;Simpson,PippaM;Holtz,MaryL;Weinstock,GeorgeM;Schwimmer,JeffreyB;Salzman,NitaH
• 通讯作者: Salzman,NitaH