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/摘要蛋白质能源营养不良（PEU）隐含在五岁以下的全球死亡中的一半，并且仍然是当今儿科最紧迫的挑战之一。 PEU开始运动肝脏的恶性循环功能异常，进一步侵蚀健康。例如，肠胆汁酸明显降低 PEU的儿童，导致饮食中的脂肪痛苦不佳和体重增加受损。在严重的情况下，维生素K- 独立的凝血病会导致灾难性的出血。 PEU改变这两个机制过程未知，尽管证据暗示了营养感应的核接收器，但Farnesoid X 受体（FXR）和过氧化物组增殖物激活受体（PPAR）α。 FXR被胆汁在美联储状态激活酸，而PPARα通过脂解的产物在禁食状态下激活。这些受体调节胆汁酸稳态和其他肝功能，竞争与许多相同的相同启动子区域结合转录效应。编码FXR的基因中突变的儿童也具有维生素K非依赖性凝血病与多种凝血因子的转录表示，包括纤维蛋白原，暗示，暗示了FXR PEU凝血病中的信号传导。为了研究核接收器在这两个肝功能中的作用，我们检查了早期PEU的小鼠模型，每种PEU的模型都表现出全球改进的胆汁酸和凝血病。我们年轻小鼠中的基因表达模式表明PPARα激活，FXR信号丧失，以及促进胆汁酸合成和凝结的基因的转录表示。基于这些调查结果是，我们的假设是PEU中产生的脂解产物的PPARα激活转录反映胆汁酸合成中的关键基因，导致肠道胆酸降低体重增加受损。此外，我们假设激活的PPARα从共享中取代FXR DNA启动子区域，通过减少FXR依赖性基因的转录来介导凝血病。该假设将以两个具体的目的进行检验。在AIM 1中，PEU和健康的野生型小鼠接受治疗 PPARα激动剂或拮抗剂以及PEU和健康的PPARα-/ - 小鼠将用于确定PPARα如何通过qPCR，胆汁酸浓度来驱动基因表达的变化 LC-MS/MS和随着时间的推移增长障碍。在AIM 2中，用PPARα和FXR激动剂处理的野生型小鼠以及拮抗剂将用于确定两个核接收器之间的竞争性DNA结合是否通过FXR依赖性凝血因子的转录表示导致凝血病变。这些研究将采用CHIP-SEQ，RNA-SEQ和血浆凝血测量。我们的预期结果是由核马介导的新分子链接的表征，在调节之间胆汁酸稳态和凝结，两者在PEU中都在病理上改变。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，最终可能是由于各种医学和社会经济原因，可承受体重减轻的儿童。 Geoffrey A. Preidis，医学博士，博士目前是儿科胃肠病学，肝病学和营养的研究员在贝勒医学院。他在宏基因组学，全球健康和营养方面有很强的出版记录使用PEU的儿童和动物模型进行研究。他的长期目标是成为一名独立的NIH资助生理科学家研究了生命早期营养剥夺引起的合并症。这些研究 AIMS通过在儿科胃肠病学和宏基因组学的研究生工作，对核受体生物学的新培训以及高级应用吞吐量测序和生物信息学分析。培训计划的其他关键要素包括：1）具有专业知识的国际认可，独立资助的调查员的遗产和咨询团队在开发计划的各个方面，包括David Moore博士。（核受体生物学），亚历山大 Milosavljevic博士（全基因组生物信息学）和医学博士Robert Shulman（临床翻译研究）和儿科胃肠病学家的学术职业发展）； 2）核接收器的高级课程贝勒医学学院生物医学科学研究生院的生物学和生物信息学 Spring Harbor实验室，FaseB科学研究会议和Keystone研讨会； 3）学术旨在促进独立的活动。 PI的培训环境是一项首要的学术研究机构与世界上最大的医疗中心，美国最大的儿童医院和 NIH资助的得克萨斯州医疗中心消化疾病中心。这个环境将提供协作，支持和产品氛围，以支持完成所有研究目标和发展目标提议的时间表。总而言之，该培训计划将使PI进入成功职业的直接途径作为独立研究者，同时识别PEU中肝功能障碍的新途径开发并最终可以预防和治疗。