Role of the bile acid activated receptors FXR and TGR5 in Total Parenteral Nutrition associated hepatic and gut disease

胆汁酸激活受体 FXR 和 TGR5 在全肠外营养相关肝脏和肠道疾病中的作用

• 批准号: 10390680
• 负责人: Ajay K. Jain
• 金额: $ 7.18万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390680
• 关键词: Address; Agonist; Animals; Award; Bacteroidetes; Bile Acids; Bypass; COVID-19; Data; Data Analyses; Disease; Endotoxins; Enteral; Environment; Etiology; FGF19 gene; Funding; GLP-2; GPBAR1 gene; Goals; Grant; Guidelines; Hepatic; Impairment; Individual; Infusion procedures; Injury; Institution; Interruption; Intravenous; Investigation; Length of Stay; Link; Liver; Manuscripts; Mediating; Outcome; Pathology; Pathway interactions; Patients; Physicians; Policies; Proteins; Publications; Research; Research Technics; Role; Saints; Scientist; Testing; Total Parenteral Nutrition; Training; United States; United States National Institutes of Health; Universities; career; career development; cytokine; design; experimental study; farnesoid X-activated receptor; glucagon-like peptide 1; gut microbiota; gut-liver axis; novel strategies; nutrition; patient home care; receptor; response; skills

PROJECT SUMMARY / ABSTRACT Total Parenteral nutrition (TPN) provides nutrition by bypassing the gut. It is a crucial lifesaving therapy for over 30,000 individuals in the US permanently dependent on TPN. Several fold higher numbers of patients require TPN for a prolonged duration. It is also used worldwide. Unfortunately, its use causes potentially fatal liver and gut injury from a likely multifactorial, yet unknown etiology. No established ameliorative strategies exist. Dr. Jain’s long-term career goal is to become an independent NIH-funded physician scientist in the niche field to develop strategies to ameliorate TPN associated pathology. His focus is on understanding the interplay of bile acid regulated pathways that modulate the Gut-Liver axis during TPN infusion. The objective of the K08 proposal was to obtain training in designing hypothesis driven proposals, acquiring research techniques, performing experiments, critically analyzing data and developing skills to overcome pitfalls. He has obtained very encouraging data resulting in many manuscripts and several national awards, helping advance his academic pursuits. Indeed, with this award he has also been generating a critical mass of data and publications to apply for an NIH R01 grant, however, his trajectory was interrupted due a halt in studies for almost 12 months, per University policies and guidelines, in response to COVID-19 during most of 2020 and the beginning of 2021. The university has now, in 2021 allowed the studies to continue. As detailed in his research plan; with Aim 1 he evaluated gut and hepatic outcomes in TPN infused animals given Farnesoid X Receptor (FXR) agonists and will further assess impact from FXR regulated downstream protein FGF19 to determine additional mechanistic links. Aim 2 relates to exploring the mechanisms by which the TGR5-GLP axis additionally regulates TPN pathology. He has tested responses to intravenously infused Glucagon Like Peptide-2 (GLP-2) and enterally administered TGR5 agonist and will further assess GLP-1 in animals receiving TPN. Aim 3 addresses alteration in gut microbiota, specifically a clonal Bacteroidetes proliferation leading to impaired gut integrity and thus endotoxin and cytokine mediated injury in animals on TPN. Each of his aims have used several highly novel strategies. These aims have supported Dr. Jain’s career development by providing training in mechanistic aspects of TPN pathobiology as related to the roles of bile acid regulated pathways. Finally, Dr. Jain continues to have a research environment in a preeminent academic research institution (Saint Louis University) with leaders in the field at the SLU Liver center, a designated center of excellence. Most importantly, Dr. Jain is a candidate who has shown extreme determination to advance his research and has full institutional commitment to enable him to succeed.

项目摘要 /摘要 肠胃外营养（TPN）通过绕过肠道提供营养。这是至关重要的救生疗法 美国30,000个人永久取决于TPN。数量更高的患者需要 TPN持续时间延长。它也在全球使用。不幸的是，它的使用会导致潜在的致命肝脏和 可能多因素但未知的病因受到肠道损伤。没有建立的改善策略。 Jain博士的长期职业目标是成为一名独立的NIH资助的物理科学家 利基领域制定改善TPN相关病理的策略。他的重点是理解 在TPN输注过程中调节肠肝轴的胆汁酸调节途径的相互作用。目标 K08的建议是获得设计假设驱动建议的培训，并获得了研究 技术，执行实验，批判性分析数据和开发技能以克服陷阱。他有 获得了非常令人鼓舞的数据，从而获得了许多手稿和几个国家奖项，从而有助于进步 他的学术追求。确实，通过这个奖项，他还产生了大量数据， 出版物要申请NIH R01赠款，但是，由于研究的停顿，他的轨迹被打断了 根据大学的政策和准则，将近12个月，在2020年的大部分时间里对Covid-19和 2021年初。该大学现已在2021年继续进行研究。 正如他的研究计划中所详述的；用AIM 1，他评估了TPN感染的肠道和肝脏结果 给出了Farnesoid X受体（FXR）激动剂的动物，并将进一步评估FXR调节的影响 下游蛋白FGF19确定其他机械连接。目标2与探索 TGR5-GLP轴另外调节TPN病理的机制。他已经测试了对 静脉注入胰高血糖素（例如肽-2（GLP-2））和肠内给药的TGR5激动剂，将 在接受TPN的动物中进一步评估GLP-1。 AIM 3解决了肠道微生物群的改变，特别是 克隆细菌植物的增殖导致肠道完整性受损，因此内毒素和细胞因子介导 动物在TPN上受伤。他的每个目标都使用了几种高度新颖的策略。这些目标有 通过在TPN病理学的机理方面提供培训作为支持Jain博士的职业发展 与胆汁酸调节途径的作用有关。 最后，Jain博士继续在杰出的学术研究中拥有研究环境 机构（圣路易斯大学）与SLU肝脏中心的领域领导人，指定的中心 卓越。最重要的是，Jain博士是一位候选人，他表现出极端的决心来推进他的 研究并具有完全的机构承诺，使他能够成功。