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.

项目概要/摘要 全肠外营养 (TPN) 通过绕过肠道提供营养。这是一种至关重要的救生疗法 美国有 30,000 人永久依赖 TPN。需要的患者数量增加几倍 TPN 持续时间较长。它也在世界范围内使用。不幸的是，它的使用可能会导致致命的肝脏和 肠道损伤可能是由多因素造成的，但病因尚不清楚。不存在既定的改善策略。 Jain 博士的长期职业目标是成为一名由 NIH 资助的独立医师科学家 利基领域制定改善 TPN 相关病理的策略。他的重点是理解 TPN 输注期间调节肠-肝轴的胆汁酸调节途径的相互作用。目标 K08 提案的目的是获得设计假设驱动提案、获取研究的培训 技术、进行实验、批判性地分析数据并培养克服陷阱的技能。他有 获得了非常令人鼓舞的数据，产生了许多手稿和多个国家奖项，帮助推进 他的学术追求。事实上，凭​​借这个奖项，他还生成了大量的数据和 发表文章申请 NIH R01 资助，然而，由于研究的停止，他的轨迹被打断了 根据大学政策和指南，在 2020 年的大部分时间和 2021 年初。该大学现已允许在 2021 年继续进行研究。 正如他的研究计划中详细说明的那样；根据目标 1，他评估了 TPN 输注的肠道和肝脏结果 给予 Farnesoid X 受体 (FXR) 激动剂的动物，并将进一步评估 FXR 监管的影响 下游蛋白质 FGF19 以确定其他机制联系。目标 2 涉及探索 TGR5-GLP 轴另外调节 TPN 病理的机制。他测试了以下反应 静脉输注胰高血糖素样肽-2 (GLP-2) 和肠内施用 TGR5 激动剂，并将 进一步评估接受 TPN 的动物中的 GLP-1。目标 3 解决肠道微生物群的改变，特别是 克隆性拟杆菌增殖导致肠道完整性受损，从而导致内毒素和细胞因子介导 TPN 对动物造成的伤害。他的每个目标都使用了几种非常新颖的策略。这些目标有 通过提供 TPN 病理学机械方面的培训来支持 Jain 博士的职业发展 与胆汁酸调节途径的作用有关。 最后，Jain 博士继续拥有卓越的学术研究环境 机构（圣路易斯大学），SLU 肝脏中心拥有该领域的领导者，该中心是指定的中心 卓越。最重要的是，贾恩博士是一位表现出极大决心推进自己事业的候选人。 研究并有充分的机构承诺使他能够取得成功。