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

基本信息

  • 批准号:
    10491865
  • 负责人:
  • 金额:
    $ 37.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-22 至 2026-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY / ABSTRACT Bowel resection leads to the devastating condition of Short Bowel Syndrome (SBS). SBS patients cannot maintain nutrition through regular enteral nutrition (EN) due to insufficient intestines. Such patients, in the absence of EN, require intravenous nutrition via a process called Total Parenteral nutrition (TPN) for survival. Worldwide, tens of thousands of patients require TPN. Despite the lifesaving TPN, side effects in SBS include potentially fatal liver and gut injury. Although, many researchers have focused on the detrimental effects of the constituents of TPN, results from our published studies highlight our novel hypothesis that the state of luminal content deprivation in SBS, disrupts the normal gut derived signals and drives injury mechanisms in SBS. Our published data shows that during EN, as part of normal enterohepatic circulation of bile acids (BA), activation of gut Farnesoid X Receptor (FXR) by BA results in release of Fibroblast Growth Factor 19 (FGF19). FGF19 regulates hepatic BA, cholestasis, lipid, and glucose homeostasis. Due to a lack of gut FXR activation in SBS we hypothesize that the FXR-FGF19 signaling axis is impaired. We have also published that BA prevent gut atrophy by enhancing Glucagon Like Peptides (GLPs). GLPs are regulated via BA activated gut receptor TGR5. While GLP-2 is a gut trophic factor; GLP-1 modulates hepatic steatosis, insulin, and glucose. We hypothesize that inadequate gut TGR5 activation in SBS additionally drives liver and gut injury. Novel Model: We have established a novel untethered ambulatory SBS piglet model using miniature pumps, jugular and duodenal catheters, and surgical bowel resection (SLU#2346,43-R-011) to closely recapitulate human SBS. Proof of Concept: We have published that in animals on TPN without bowel resection (and not receiving EN), treatment with gut FXR agonist, Chenodeoxycholic acid (CDCA) or gut TGR5 agonist Oleanolic Acid (OA), as well as intravenous FGF19 and GLP-1/GLP-2 can prevent liver and gut injury. Importantly, we have shown inadequate gut FXR and gut TGR5 activation and decreased FGF19, GLP-1/GLP-2 in SBS animals. In pilot studies we have noted hepatic and gut protection with CDCA and OA treatment in SBS. Thus, our central premise is to critically understand alteration in gut FXR and gut TGR5 driven signaling in SBS and to test if its restoration in SBS animals mitigates injury. As detailed in the research plan, we will test our hypothesis under the following aims. With Aim 1 we will critically test the roles of intravenous FGF19 and the gut FXR agonist, CDCA on liver injury in SBS. We will analyze serum, histology, key receptors, and transporters along the FXR-FGF19 axis to understand mechanistic links. With Aim 2 we will deliver the gut TGR5 agonist, OA as well as GLP-1/GLP-2 in SBS animals and explore TGR5-GLP axis driven protective mechanisms in SBS, assessing serology, histology, gut trophic factors, morphometrics and gene expression. This project, using a highly translatable SBS model will help advance strategies to mitigate serious complications and provide key insights into drivers of injury in SBS.
项目摘要/摘要

项目成果

期刊论文数量(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
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:
    $ 37.88万
  • 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:
    $ 37.88万
  • 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:
    $ 37.88万
  • 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:
    $ 37.88万
  • 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:
    $ 37.88万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 37.88万
  • 项目类别:

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