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
基本信息
- 批准号:10390680
- 负责人:
- 金额:$ 7.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAgonistAnimalsAwardBacteroidetesBile AcidsBypassCOVID-19DataData AnalysesDiseaseEndotoxinsEnteralEnvironmentEtiologyFGF19 geneFundingGLP-2GPBAR1 geneGoalsGrantGuidelinesHepaticImpairmentIndividualInfusion proceduresInjuryInstitutionInterruptionIntravenousInvestigationLength of StayLinkLiverManuscriptsMediatingOutcomePathologyPathway interactionsPatientsPhysiciansPoliciesProteinsPublicationsResearchResearch TechnicsRoleSaintsScientistTestingTotal Parenteral NutritionTrainingUnited StatesUnited States National Institutes of HealthUniversitiescareercareer developmentcytokinedesignexperimental studyfarnesoid X-activated receptorglucagon-like peptide 1gut microbiotagut-liver axisnovel strategiesnutritionpatient home carereceptorresponseskills
项目摘要
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
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。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ajay K. Jain其他文献
Thrombus Entrapment by a Novel Mesh-Covered Stent in ST-Segment Elevation Myocardial Infarction
- DOI:
10.1016/j.jacc.2011.01.079 - 发表时间:
2011-11-22 - 期刊:
- 影响因子:
- 作者:
Ajay K. Jain;Martin T. Rothman - 通讯作者:
Martin T. Rothman
Bacterial skin infections in cirrhotics
- DOI:
10.1016/j.jceh.2013.02.221 - 发表时间:
2013-03-01 - 期刊:
- 影响因子:
- 作者:
Mayank Jain;Ajay K. Jain;Shohini Sircar;Chandrashekhar Waghmare;Sagar Adkar - 通讯作者:
Sagar Adkar
Kinetics of n-propylaminolysis of some oxime ethers in 1:1 aqueous acetonitrile
- DOI:
10.1007/bf02069217 - 发表时间:
1987-03-01 - 期刊:
- 影响因子:1.700
- 作者:
Ajay K. Jain;V. K. Velu;K. N. Sarma - 通讯作者:
K. N. Sarma
859 BILIARY ATRESIA THROUGH TARGETED ENDOTHELIAL DESTRUCTION (BATTED) PRESENTS A NOVEL LARGE ANIMAL MODEL, RECAPITULATING HUMAN DISEASE
- DOI:
10.1016/s0016-5085(24)04045-9 - 发表时间:
2024-05-18 - 期刊:
- 影响因子:
- 作者:
Kento Kurashima;Arun Verma;Si-Min Park;Marzena Swiderska-Syn;Sree L. Kolli;David J. Gosser;Jasmine Carter;Shaurya Mehta;Austin Sims;Jeffrey Teckman;Mustafa Nazzal;John Long;Chandrashekhara Manithody;Shin Miyata;Ajay K. Jain - 通讯作者:
Ajay K. Jain
Increased morbidity in acute viral hepatitis with glucose-6-phosphate dehydrogenase deficiency
- DOI:
10.1007/s12664-012-0226-9 - 发表时间:
2012-08-07 - 期刊:
- 影响因子:2.100
- 作者:
Ajay K. Jain;Shohini Sircar;Mayank Jain;Sagar Adkar;Chandrashekhar Waghmare;Fatema Chahwala - 通讯作者:
Fatema Chahwala
Ajay K. Jain的其他文献
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{{ truncateString('Ajay K. Jain', 18)}}的其他基金
Role of intestinal microbiota in driving injury mechanisms in short bowel syndrome
肠道微生物群在驱动短肠综合征损伤机制中的作用
- 批准号:
10580044 - 财政年份:2022
- 资助金额:
$ 7.18万 - 项目类别:
Role of intestinal microbiota in driving injury mechanisms in short bowel syndrome
肠道微生物群在驱动短肠综合征损伤机制中的作用
- 批准号:
10433531 - 财政年份:2022
- 资助金额:
$ 7.18万 - 项目类别:
Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome
胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用
- 批准号:
10683281 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome
胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用
- 批准号:
10343091 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
Role of bile acid receptors FXR and TGR5 in preventing injury in short bowel syndrome
胆汁酸受体 FXR 和 TGR5 在预防短肠综合征损伤中的作用
- 批准号:
10491865 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
Role of gut microbiota in total parenteral nutrition associated injury
肠道微生物群在全肠外营养相关损伤中的作用
- 批准号:
9910396 - 财政年份:2019
- 资助金额:
$ 7.18万 - 项目类别:
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