Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease

定义 Fontan 姑息治疗或炎症性肠道疾病后蛋白质丢失性肠病的淋巴基础

基本信息

  • 批准号:
    10325733
  • 负责人:
  • 金额:
    $ 78.75万
  • 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:
    2021-09-30 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT Protein-losing enteropathy (PLE) is the term given to the pathological phenomenon of protein dumping from the systemic circulation into the intestinal lumen. Various degrees of PLE are observed in a variety of otherwise unrelated diseases. For instance, PLE is a complication of the life-saving Fontan palliation procedure performed on children born with only a single ventricle of the heart to create a vascular diversion to the lungs to promote improved oxygenation of blood. Fontan-associated PLE is linked with high mortality: 30-50% over 5- to 10-years. Yet, PLE remains understudied. The dominant causal mechanisms underlying PLE appear to relate to (1) loss of barrier integrity at the intestinal epithelium or (2) functional disturbance of the lymphatic vasculature. Intestinal epithelial cell erosion would expose proteinaceous tissue fluid to the intestinal lumen. Furthermore, poor epithelial intercellular junctions might allow for the contents of the lamina propria interstitium to leak into the intestinal lumen. With respect to lymphatics, failure of lymph to flow away from the intestine uni-directionally toward the heart and instead to flow backwards from the body trunk toward the intestine with sufficient force to break across the epithelium may be a major cause of PLE. The literature presents Fontan palliation-associated PLE as a problem driven by lymphatic backflow, whereas PLE in IBD (such as Crohn's disease) is presented as being of mixed etiology that involves breach of epithelial integrity with possible additional contributions stemming from lymphatic dysfunction. However, it is acknowledged in the literature that the full basis of PLE in any of these conditions is uncertain and that there are several reasons why the current explanations may be questioned. We will carry out focused research on PLE that includes studies involving human participants as well as studies in experimental animal models. Our hypotheses are, first, that the lymphatic vasculature is a primary player in PLE affecting Fontan patients and IBD patients, and second, that the lymphatic vasculature must receive “two hits” to drive sufficient backflow of lymph to cause outflow from the intestinal barrier. The first of these hits has already been considered (but not completely tested) in the context of Fontan palliation: increased pressure within the chain of lymphangions (vessel units between lymphatic valves). We propose this second hit is an inflammatory signal that negatively affects lymphatic valves. The two-hit model may resolve a confusing observation in Fontan patients with PLE wherein treatments with steroids like budesonide can be effective. A steroid seems unlikely to strongly alter pressure in the venous and lymphatic systems, but it is easy to envision how steroids may help by reducing adverse inflammatory signalling associated with valve failure. If this model is correct, a path to therapies not previously considered to treat PLE may become evident.
摘要 蛋白丢失性肠病(PLE)是指蛋白质从肠道排出的病理现象。 体循环进入肠腔。不同程度的PLE被观察到在各种其他 无关的疾病。例如,PLE是一个并发症的救生丰唐姑息程序进行 对出生时只有一个心室的孩子,以创造一个血管转移到肺部, 改善血液的氧合。Fontan相关的PLE与高死亡率有关:5至10年内为30-50%。 然而,PLE仍然研究不足。PLE的主要因果机制似乎与(1)损失 肠上皮屏障完整性或(2)淋巴管系统功能紊乱。肠 上皮细胞侵蚀将使蛋白质组织液暴露于肠腔。此外,穷人 上皮细胞间连接可能允许固有层的内容物渗漏到 肠腔淋巴液不能从肠道单向流出, 相反,它会以足够的力量从身体躯干流向肠道, 上皮破裂可能是PLE的主要原因。文献显示Fontan姑息相关 PLE是由淋巴回流引起的问题,而IBD(如克罗恩病)中的PLE则表现为 具有混合病因,涉及破坏上皮完整性,可能有其他贡献, 淋巴功能紊乱然而,在文献中承认,在这些文献中的任何一个中的PLE的全部基础都是不可靠的。 他说,情况是不确定的,有几个原因可以质疑目前的解释。我们 将对PLE进行重点研究,包括涉及人类参与者的研究以及 实验动物模型。我们的假设是,第一,淋巴管系统是一个主要的球员在PLE 影响Fontan患者和IBD患者,第二,淋巴管系统必须接受“两次打击” 以驱动足够的淋巴回流,从而导致从肠屏障流出。第一次袭击已经 在Fontan缓解的背景下考虑(但未完全测试): 淋巴管链(淋巴管瓣之间的血管单位)。我们认为第二次袭击是一次煽动性的袭击 对淋巴阀有负面影响的信号。两次打击模型可以解决Fontan中令人困惑的观察结果 其中使用类固醇如布地奈德治疗可能有效的PLE患者。类固醇似乎不太可能 强烈改变静脉和淋巴系统的压力,但很容易想象类固醇如何通过 减少与瓣膜衰竭相关的不良炎症信号传导。如果这个模型是正确的, 以前没有考虑过的治疗PLE的方法可能变得明显。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Gwendalyn J Randolph其他文献

Proliferating macrophages prevail in atherosclerosis
增殖的巨噬细胞在动脉粥样硬化中占优势
  • DOI:
    10.1038/nm.3316
  • 发表时间:
    2013-09-06
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Gwendalyn J Randolph
  • 通讯作者:
    Gwendalyn J Randolph

Gwendalyn J Randolph的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Gwendalyn J Randolph', 18)}}的其他基金

Mechanisms that alter lymphatic transport in inflammatory bowel disease
改变炎症性肠病淋巴运输的机制
  • 批准号:
    10420703
  • 财政年份:
    2022
  • 资助金额:
    $ 78.75万
  • 项目类别:
Mechanisms that alter lymphatic transport in inflammatory bowel disease
改变炎症性肠病淋巴运输的机制
  • 批准号:
    10565928
  • 财政年份:
    2022
  • 资助金额:
    $ 78.75万
  • 项目类别:
Imaging and Surgery Core
影像和手术核心
  • 批准号:
    10674672
  • 财政年份:
    2022
  • 资助金额:
    $ 78.75万
  • 项目类别:
Interplay between meningeal lymphatics, high-density lipoproteins and border macrophages in cerebral amyloid angiopathy
脑淀粉样血管病中脑膜淋巴管、高密度脂蛋白和边界巨噬细胞之间的相互作用
  • 批准号:
    10674681
  • 财政年份:
    2022
  • 资助金额:
    $ 78.75万
  • 项目类别:
Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease
定义 Fontan 姑息治疗或炎症性肠道疾病后蛋白质丢失性肠病的淋巴基础
  • 批准号:
    10661777
  • 财政年份:
    2021
  • 资助金额:
    $ 78.75万
  • 项目类别:
Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine
限制肠道微生物信号传播的肠道区域特异性机制
  • 批准号:
    10283039
  • 财政年份:
    2021
  • 资助金额:
    $ 78.75万
  • 项目类别:
Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine
限制肠道微生物信号传播的肠道区域特异性机制
  • 批准号:
    10665044
  • 财政年份:
    2021
  • 资助金额:
    $ 78.75万
  • 项目类别:
DIFFERENTIATION AND FUNCTION OF MONOCYTES AND MACROPHAGES
单核细胞和巨噬细胞的分化和功能
  • 批准号:
    10158696
  • 财政年份:
    2020
  • 资助金额:
    $ 78.75万
  • 项目类别:
Cellular and spatial mechanisms underlying how inflammatory cytokines impact postprandial glucose responses in health and disease
炎症细胞因子如何影响健康和疾病中餐后葡萄糖反应的细胞和空间机制
  • 批准号:
    10064841
  • 财政年份:
    2020
  • 资助金额:
    $ 78.75万
  • 项目类别:
Lymphatic remodeling and transport of dietary fats in short gut syndrome
短肠综合征中的淋巴重塑和膳食脂肪运输
  • 批准号:
    10579922
  • 财政年份:
    2019
  • 资助金额:
    $ 78.75万
  • 项目类别:

相似海外基金

Implication search for peripheral blood circulation cancer cellsas a Liquid biopsy target
外周血循环癌细胞作为液体活检目标的意义研究
  • 批准号:
    21H03021
  • 财政年份:
    2021
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Feasibility study to reach 'market readiness' with Recocoa's unique cacao based health bar, which is the only health nutrition bar which meets the European Health Claim (EFSA) in improving blood circulation by maintaining the elasticity of blood vessels.
Recocoa 独特的可可健康棒进行了“市场准备”的可行性研究,该健康棒是唯一符合欧洲健康声明 (EFSA) 通过保持血管弹性改善血液循环的健康营养棒。
  • 批准号:
    106360
  • 财政年份:
    2020
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Collaborative R&D
Feasibility study to reach 'market readiness' with Recocoa's unique cacao based health bar, which is the only health nutrition bar which meets the European Health Claim (EFSA) in improving blood circulation by maintaining the elasticity of blood vessels.
Recocoa 独特的可可健康棒进行了“市场准备”的可行性研究,该健康棒是唯一符合欧洲健康声明 (EFSA) 通过保持血管弹性改善血液循环的健康营养棒。
  • 批准号:
    72375
  • 财政年份:
    2020
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Feasibility Studies
Quantitative evaluation of blood circulation by deep learning in short time DCE-MRI
短时间深度学习DCE-MRI对血液循环的定量评估
  • 批准号:
    20K08041
  • 财政年份:
    2020
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Evaluation of the micro blood circulation of the oral free flaps by indocyanin green near-infrared fluorescence angiography
吲哚青绿近红外荧光血管造影评价口腔游离皮瓣的微血循环
  • 批准号:
    19K10299
  • 财政年份:
    2019
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Establishment of a new treatment for pancreatic cancer by controlling immune response avoidance of blood circulation cancer stem cells
通过控制血液循环癌症干细胞的免疫反应避免建立胰腺癌新疗法
  • 批准号:
    19K09139
  • 财政年份:
    2019
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of ICG fluorescence contrast imaging analysis system specialized for evaluation of peripheral tissue blood circulation
开发专门评估末梢组织血液循环的ICG荧光对比成像分析系统
  • 批准号:
    19K18925
  • 财政年份:
    2019
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The Hemopurifier Device for Targeted Removal of Breast Cancer Exosomes from the Blood Circulation
用于从血液循环中靶向去除乳腺癌外泌体的血液净化器装置
  • 批准号:
    9620493
  • 财政年份:
    2018
  • 资助金额:
    $ 78.75万
  • 项目类别:
Development of the small blood circulation simulator to deepen the non-clinical evaluation of medical devices
开发小型血液循环模拟器深化医疗器械非临床评价
  • 批准号:
    18H03555
  • 财政年份:
    2018
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Experimental analysis of conservative therapy for blood circulation disorders using multifaceted optical measurement of nerve activity and peripheral blood flow
多层面光学测量神经活动和外周血流量保守治疗血液循环障碍的实验分析
  • 批准号:
    17K10764
  • 财政年份:
    2017
  • 资助金额:
    $ 78.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了