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

项目概要/摘要 全胃肠外营养（TPN）通过绕过肠道提供营养。这是一个至关重要的救生疗法， 美国有30，000人永久依赖TPN。几倍以上的患者需要 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 可能是多因素导致的肠道损伤但病因不明没有既定的改善策略。 Jain博士的长期职业目标是成为一名独立的NIH资助的内科科学家， 利基领域，制定战略，以改善TPN相关的病理。他的重点是了解 TPN输注期间调节肠-肝轴的胆汁酸调节途径的相互作用。客观 K 08提案的目的是获得设计假设驱动提案的培训， 技术，进行实验，批判性地分析数据和发展技能，以克服陷阱。他 获得了非常令人鼓舞的数据，产生了许多手稿和几个国家奖项，帮助推进 他的学术追求事实上，凭借这一奖项，他还产生了大量的数据， 然而，他的研究轨迹因研究停止而中断， 近12个月，根据大学的政策和指导方针，在2020年的大部分时间内应对COVID-19， 2021年初。该大学现在已经在2021年允许继续进行研究。 如他的研究计划所述;他评价了目标1中TPN输注的肠道和肝脏结局 给予法尼醇X受体（FXR）激动剂的动物，并将进一步评估FXR调节的 下游蛋白FGF 19以确定额外的机制联系。目标2涉及探索 TGR 5-GLP轴额外调节TPN病理学的机制。他测试了 静脉内输注胰高血糖素样肽-2（GLP-2）和肠内施用的TGR 5激动剂，并将 进一步评估接受TPN的动物中的GLP-1。目标3解决了肠道微生物群的改变，特别是 克隆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的 TPN治疗动物的损伤。他的每一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病理生物学机制方面的培训，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博士继续在一个卓越的学术研究环境中进行研究。 该机构（圣刘易斯大学）与SLU肝脏中心的领域领导者， 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。

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.