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Nuclear receptor mediated bile acid alterations and coagulopathy in protein-energy undernutrition

蛋白质能量营养不良中核受体介导的胆汁酸改变和凝血病

基本信息

批准号：
10241927
负责人：
Geoffrey A Preidis
金额：
$ 16.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241927
关键词：
5 year old 7alpha hydroxylase Address Advisory Committees Affect Agonist Anemia Animal Model Atmosphere Autophagocytosis Bile Acid Biosynthesis Pathway Bile Acids Binding Bioinformatics Biology Blood Coagulation Disorders Blood Coagulation Factor Body Weight decreased CYP7A1 gene Cessation of life ChIP-seq Child Childhood Cholesterol Clinical Coagulation Process Contusions DNA DNA Binding Detection Development Development Plans Diet Dietary Fats Digestion Digestive System Disorders Doctor of Medicine Doctor of Philosophy Elements Environment Enzymes Etiology Exhibits Fasting Fat-Soluble Vitamin Fatty acid glycerol esters Feces Fibrinogen Fostering Foundations Funding Gastroenterologist Gastroenterology Gene Expression Gene Expression Profile Genes Genetic Transcription Gluconeogenesis Goals Growth Health Hemorrhage Hepatology High-Throughput Nucleotide Sequencing Homeostasis Hospital Costs Impairment Institution International Intestines Knowledge Laboratories Lead Life Link Lipolysis Liver Malabsorption Syndromes Malnutrition Measurement Measures Mediating Medical Medical Care Costs Medical center Medicine Mentorship Metabolic Pathway Metabolism Metagenomics Micelles Mixed Function Oxygenases Modeling Molecular Motion Mus Mutation Nuclear Hormone Receptors Nuclear Receptors Nutrient Nutritional Study Nutritional status Outcome PPAR alpha Pathologic Pathway interactions Pediatric Hospitals Pediatrics Pharmacology Physicians Physiological Physiological Processes Plasma Process Promoter Regions Proteins Prothrombin time assay Publications Quality of life Receptor Signaling Regulation Repression Research Research Personnel Role Route Schools Science Scientist Signal Transduction Site Small Intestines Sterols Testing Texas Therapeutic Time TimeLine Tissues Training Translational Research United States United States National Institutes of Health Vitamin Deficiency Vitamin K Weight Gain Western Blotting Wild Type Mouse Work absorption activation product base career career development college comorbidity design detection of nutrient fatty acid oxidation gene repression genome-wide global health gut bacteria healthy weight improved liver function loss of function mutation mortality mouse model novel novel therapeutics nutrient deprivation nutrition oxysterol 7-alpha-hydroxylase prevent promoter receptor response socioeconomics symposium targeted treatment transcriptome sequencing young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Protein-energy undernutrition (PEU) is implicated in half of all global deaths under five years of age and remains one of the most pressing challenges in pediatrics today. PEU sets into motion a vicious cycle of liver function abnormalities that further erode health. For example, intestinal bile acids are markedly reduced in children with PEU, resulting in poor dietary fat absorption and impaired weight gain. In severe cases, vitamin K- independent coagulopathy can lead to catastrophic bleeding. Mechanisms by which PEU alters these two processes are unknown, although evidence implicates the nutrient-sensing nuclear receptors, farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)α. FXR is activated in the fed state by bile acids, while PPARα is activated in the fasted state by products of lipolysis. These receptors regulate bile acid homeostasis and other liver functions, competing for binding to many of the same promoter regions with opposite transcriptional effects. Children with mutations in the gene encoding FXR also have vitamin K-independent coagulopathy with transcriptional repression of multiple coagulation factors including fibrinogen, implicating FXR signaling in the coagulopathy of PEU. To investigate the role of nuclear receptors in these two liver functions, we examined mouse models of early-life PEU, each of which exhibits globally decreased bile acids and coagulopathy. Gene expression patterns in our young adult mice demonstrate Pparα activation, Fxr signal loss, and transcriptional repression of genes that promote bile acid synthesis and coagulation. Based on these findings, our hypothesis is that Pparα activation by products of lipolysis generated in PEU transcriptionally represses key genes in bile acid synthesis leading to decreased intestinal bile acids and impaired weight gain. Furthermore, we hypothesize that activated Pparα displaces Fxr from shared DNA promoter regions, mediating coagulopathy by decreasing transcription of Fxr-dependent genes. This hypothesis will be tested with two specific aims. In Aim 1, PEU and healthy wild type mice treated with Pparα agonist or antagonist, along with PEU and healthy Pparα-/- mice, will be used to determine how Pparα drives changes in the expression of genes that regulate bile acid pool size by qPCR, bile acid concentrations by LC-MS/MS, and growth impairment over time. In Aim 2, wild type mice treated with Pparα and Fxr agonists and antagonists will be used to determine whether competitive DNA binding between the two nuclear receptors results in coagulopathy through transcriptional repression of Fxr-dependent coagulation factors; these studies will employ ChIP-seq, RNA-seq, and plasma coagulation measurements. Our expected outcomes are characterization of a novel molecular link, mediated by nuclear hormone receptors, between the regulation of bile acid homeostasis and coagulation, both of which are pathologically altered in PEU. These studies will provide the foundation for developing new pharmacologic and diet-based therapeutic strategies that could ultimately be generalizable to children with weight loss due to a variety of medical and socioeconomic causes. Geoffrey A. Preidis, M.D., Ph.D. is currently a fellow in Pediatric Gastroenterology, Hepatology, and Nutrition at Baylor College of Medicine. He has a strong publication record in metagenomics, global health, and nutrition research with children and animal models of PEU. His long-term goal is to become an independent NIH-funded physician-scientist investigating co-morbidities that result from nutrient deprivation early in life. These research aims support the PI’s career development by building upon his background in pediatric gastroenterology and graduate work in metagenomics, with new training in nuclear receptor biology and advanced applications of high- throughput sequencing and bioinformatic analysis. Additional key elements of the training plan include: 1) A mentorship and advisory team of internationally recognized, independently funded investigators with expertise in all aspects of the development plan, including David Moore, Ph.D. (nuclear receptor biology), Aleksandar Milosavljevic, Ph.D. (genome-wide bioinformatics), and Robert Shulman, M.D. (clinical translational research and pediatric gastroenterologist academic career development); 2) Advanced coursework in nuclear receptor biology and bioinformatics from the Baylor College of Medicine Graduate School of Biomedical Sciences, Cold Spring Harbor Laboratory, FASEB Science Research Conferences, and Keystone Symposia; and 3) Scholarly activities designed to foster independence. The PI’s training environment is a premiere academic research institution closely allied with the world’s largest medical center, the nation’s largest children’s hospital, and the NIH-funded Texas Medical Center Digestive Disease Center. This environment will provide a collaborative, supportive, and productive atmosphere to facilitate completion of all research aims and development goals in the proposed timeline. In summary, this training plan will place the PI on a direct route to a successful career as an independent investigator while identifying novel pathways by which liver function impairments in PEU develop and may ultimately be prevented and treated.

项目摘要/摘要全球五岁以下儿童死亡中有一半与蛋白质-能量营养不良有关，仍然是当今儿科最紧迫的挑战之一。PEU启动了肝脏的恶性循环进一步损害健康的功能异常。例如，肠道胆汁酸在患有尿毒症的儿童，导致饮食脂肪吸收不良，体重增加受阻。在严重情况下，维生素K- 独立的凝血障碍可能导致灾难性的出血。PEU改变这两个因素的机制过程尚不清楚，尽管有证据表明与营养感应核受体法尼醇X有关受体和过氧化物酶体增殖物激活受体α。FXR在进食状态下被胆汁激活酸，而PPARα在脂肪分解产物中以禁食状态被激活。这些受体调节胆汁酸。动态平衡和其他肝脏功能，竞争结合到许多相同的启动子区域与相反转录效应。编码FXR基因突变的儿童也有维生素K非依赖性包括纤维蛋白原在内的多种凝血因子转录抑制的凝血病，与FXR有关 PEU凝血障碍中的信号转导。为了研究核受体在这两种肝功能中的作用，我们检查了早期PEU的小鼠模型，每一种模型都表现出胆汁酸和胆汁酸的全局下降凝血障碍。我们的年轻成年小鼠的基因表达模式显示PPARα激活，FxR信号丢失，以及促进胆汁酸合成和凝血的基因转录抑制。基于这些结果，我们的假设是PPARα的活化是由脂解产物在PEU中产生的转录抑制胆汁酸合成中的关键基因导致肠道胆汁酸减少体重增加也受到影响。此外，我们假设激活的PPARα取代了共享的FXR DNA启动子区域，通过减少FXR依赖基因的转录来介导凝血障碍。这一假设将通过两个具体目标进行检验。在目标1中，PEU和健康的野生型小鼠被 PPARα激动剂或拮抗剂，以及PEU和健康PPARα-/-小鼠将被用来确定PPARα如何通过qPCR驱动调节胆汁酸池大小的基因的表达变化，通过 LC-MS/MS，以及随时间推移的生长障碍。在目标2中，用PPARα和FxR激动剂处理的野生型小鼠拮抗剂将被用来确定两个核受体之间的竞争性DNA结合通过转录抑制依赖FXR的凝血因子导致凝血障碍；这些研究将采用CHIP-SEQ、RNA-SEQ和等离子凝血测量。我们的预期结果是核激素受体介导的一种新的分子连接的表征胆汁酸动态平衡和凝血，两者在PEU中都有病理改变。这些研究将提供开发新的药理学和基于饮食的治疗策略的基础，最终可能是适用于因各种医学和社会经济原因导致体重减轻的儿童。杰弗里·A·普雷迪斯，医学博士，目前是儿科胃肠病、肝病和营养学研究员。在贝勒医学院。他在元基因组学、全球健康和营养学方面有很好的出版记录对儿童和PEU动物模型的研究。他的长期目标是成为美国国立卫生研究院资助的独立的内科医生-科学家，研究生命早期营养匮乏引起的并存疾病。这些研究 AIMS通过在儿科胃肠病学和在元基因组学方面的研究生工作，以及核受体生物学的新培训和高科技的高级应用吞吐量测序和生物信息学分析。培训计划的其他主要内容包括：1)a) 由具有专业知识的国际公认的、独立资助的调查人员组成的导师和咨询团队在发展计划的所有方面，包括大卫·摩尔博士(核受体生物学)、亚历山大 Milosavljevic博士(全基因组生物信息学)和Robert Shulman医学博士(临床转化研究和儿科胃肠病专家学术生涯发展)；2)核受体高级课程贝勒医学院生物医学研究生院生物和生物信息学春港实验室、FASE B科学研究会议和Keystone研讨会；以及3)学术旨在促进独立的活动。少年派的训练环境是一项首屈一指的学术研究该机构与世界上最大的医疗中心、美国最大的儿童医院和美国国立卫生研究院资助的德克萨斯医疗中心消化疾病中心。该环境将提供一个协作、支持和富有成效的氛围，促进完成#年的所有研究目标和发展目标建议的时间表。总而言之，这个培训计划将使PI走上一条通往成功职业生涯的直接道路作为一名独立的研究人员，同时确定PEU患者肝功能损害的新途径发展，并可能最终被预防和治疗。