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

项目摘要/摘要 全肠外营养(TPN)通过绕过肠道提供营养。这是一种关键的拯救生命的疗法 美国有3万人永久依赖TPN。数倍以上的患者需要 持续时间较长的TPN。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 肠道损伤可能是多因素造成的，但病因不明。不存在既定的改善策略。 Jain博士的长期职业目标是成为美国国立卫生研究院资助的独立内科科学家 利基领域，开发改善TPN相关病理的策略。他的重点是理解 TPN输注过程中胆汁酸调节肠道-肝轴的相互作用。目标是 K08提案的目的是在设计假设驱动的提案、获取研究方面获得培训 技术，进行实验，批判性地分析数据，发展克服陷阱的技能。他有 获得了非常令人鼓舞的数据，获得了许多手稿和几个国家级奖项，帮助推动了 他的学术追求。事实上，有了这个奖项，他也产生了大量的数据和 然而，申请NIH R01拨款的出版物，他的轨迹因研究暂停而中断 近12个月，根据大学政策和指南，在2020年的大部分时间和 2021年初。现在，这所大学已经在2021年允许继续研究。 正如他的研究计划中详细描述的那样；与目标1一起，他评估了输注TPN的肠道和肝脏结果 给予法尼类X受体(FXR)激动剂的动物，将进一步评估FXR调节的影响 下游蛋白FGF19，以确定额外的机械连接。目标2涉及探索 TGR5-GLP轴额外调节TPN病理的机制。他测试了对以下问题的反应 静脉输注胰高血糖素样肽-2(GLP-2)和肠内注射TGR5激动剂和Will 进一步评估接受TPN的动物的GLP-1。目标3解决肠道微生物区系的变化，特别是 克隆性类杆菌增殖导致肠道完整性受损，从而内毒素和细胞因子介导 全胃肠外营养对动物的伤害。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病理生物学的机械方面的培训，支持Jain博士的职业发展 与胆汁酸调节通路的作用有关。 最后，Jain博士继续在卓越的学术研究中拥有研究环境 机构(圣路易斯大学)在SLU肝脏中心与该领域的领导者合作，SLU肝脏中心是 太棒了。最重要的是，贾恩博士是一位表现出极大决心推动他的 研究，并有充分的机构承诺，使他能够成功。

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.