Biomarkers of Alcoholic Hepatitis

酒精性肝炎的生物标志物

基本信息

  • 批准号:
    10631081
  • 负责人:
  • 金额:
    $ 60.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Abstract Our overarching goal is to develop minimally invasive approaches to better predict outcome and novel mechanisms in alcoholic hepatitis (AH). AH is characterized by acute hepatic decompensation and multiple organ failure. Although supportive care for AH has improved, short-term mortality has largely remained unchanged (30-40%) for decades. Effective approaches to predict risk hamper the treatment of AH. The hepatic extracellular matrix (ECM) responds dynamically to organ injury and ECM turnover increases; we propose to take advantage of this to develop new biomarkers for AH. The peptidome, low molecular weight peptides in biologic fluids, includes not only synthesized peptides, but fragments of degraded proteins (i.e., ‘degradome’). We hypothesize that the ECM degradome in plasma will yield new biomarkers to predict outcome and mechanisms in AH. We will test this hypothesis via the following Specific Aims: 1). To identify key changes in the peptidome as predictive biomarkers of outcome in AH. Unbiased peptidomics and multivariate analyses will identify degradomic features independently linked to prognosis. Protease activity that could produce significantly changed peptides will be predicted using Proteasix. We will also determine the mechanistic role of ECM turnover in the in parallel established models of alcohol-induced liver injury. 2) To develop probabilistic graphical models to predict outcome in AH. Whereas we expect the results of Aim 1 to establish that the peptidome profile in patients correlates with overall outcome, biomarkers alone are often insufficient to accurately predict individual patient outcome. We will therefore employ machine learning methods like probabilistic graphical models (PGMs) over mixed data types to integrate peptidomic and individual patient clinical data, into a single probabilistic graphical framework. The resulting graphs will then be used to infer causal interactions between variables, select informative biomarkers that will more specifically predict the outcome, and gain new mechanistic insight into the biology of AH (hypothesis generation). 3) To validate the use of the peptidome as a predictive tool for determining outcome in AH. Using a large prospectively-designed patient cohort with established outcomes, we will test the ability of the algorithms and biomarkers generated in this study to predict outcome. The successful completion of the proposed work will produce significant results at various levels: (1) Biomarker discovery: we will identify biomarkers and conditional biomarkers for AH prognosis. (2) Mechanistic understanding of AH: our models will generate hypotheses about the interactions between variables at different scales (molecular, individual) that will provide insights on the proteins that are involved in AH. (3) Algorithm development: through this project we will extend our mixed data graph learning algorithms to include censored variables (i.e., survival data). As a result of the above, this project is likely to yield novel diagnostic tools for AH that may also translate to other liver diseases.
摘要 我们的首要目标是开发微创方法,以更好地预测结果和新颖 酒精性肝炎的发病机制。以急性肝功能失代偿和多发性肝损伤为特征。 器官衰竭。尽管急性肝炎的支持性护理有所改善,但短期死亡率基本保持不变。 几十年来没有变化(30%-40%)。预测风险的有效方法阻碍了AH的治疗。肝病 细胞外基质(ECM)对器官损伤和ECM周转增加做出动态反应;我们建议 利用这一点,开发新的AH生物标记物。中低分子多肽的研究进展 生物流体,不仅包括人工合成的多肽,还包括降解蛋白质的片段(即“降解穹顶”)。 我们假设,血浆中的ECM降解组将产生新的生物标志物来预测结果和 在AH中的机制。我们将通过以下具体目标来检验这一假说:1)。确定关键变化 作为预测急性脑出血预后的生物标志物。无偏多肽与多变量分析 将确定与预后独立相关的退化特征。可产生的蛋白酶活性 将使用ProteaSix预测显著变化的多肽。我们还将确定 细胞外基质周转平行建立酒精性肝损伤模型。2)发展概率性 预测急性胰腺炎预后的图形模型。鉴于我们预计目标1的结果将确定 患者的多肽图谱与总体预后相关,仅有生物标记物往往不足以准确 预测个别患者的结果。因此,我们将使用概率等机器学习方法 混合数据类型上的图形模型(PGM),将多肽和个别患者的临床数据集成到 单一的概率图形框架。生成的图表随后将用于推断因果交互作用 在变量之间,选择信息丰富的生物标志物,这些标志物将更具体地预测结果,并获得新的 对AH(假设生成)生物学的机械论洞察。3)验证多肽穹顶作为 判断急性脑出血预后的预测工具。使用一个大型前瞻性设计的患者队列 已经确定的结果,我们将测试在这项研究中生成的算法和生物标记物的预测能力 结果。拟议工作的圆满完成将在各个层面产生重大成果:(1) 生物标记物发现:我们将识别预测急性髓细胞白血病预后的生物标记物和条件生物标记物。(2)机械学 对AH的理解:我们的模型将产生关于不同变量之间相互作用的假设 标度(分子,个体),将提供对与AH有关的蛋白质的洞察。(3)算法 发展:通过这个项目,我们将扩展我们的混合数据图学习算法,以包括审查 变量(即生存数据)。作为上述工作的结果,该项目很可能会产生用于AH的新的诊断工具 这也可能转化为其他肝病。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Causal Discovery in High-dimensional, Multicollinear Datasets.
高维、多重共线性数据集中的因果发现。
  • DOI:
    10.3389/fepid.2022.899655
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jia,Minxue;Yuan,DanielY;Lovelace,TylerC;Hu,Mengying;Benos,PanayiotisV
  • 通讯作者:
    Benos,PanayiotisV
LEF1 isoforms regulate cellular senescence and aging.
  • DOI:
    10.1111/acel.14024
  • 发表时间:
    2023-12
  • 期刊:
  • 影响因子:
    7.8
  • 作者:
  • 通讯作者:
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Gavin E Arteel其他文献

Gavin E Arteel的其他文献

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{{ truncateString('Gavin E Arteel', 18)}}的其他基金

The role of matrix-bound microvesicles in alcohol-related liver disease
基质结合微泡在酒精相关性肝病中的作用
  • 批准号:
    10582800
  • 财政年份:
    2023
  • 资助金额:
    $ 60.14万
  • 项目类别:
Novel Biomarkers for Post-Liver Transplant NASH Fibrosis
肝移植后 NASH 纤维化的新型生物标志物
  • 批准号:
    10518842
  • 财政年份:
    2022
  • 资助金额:
    $ 60.14万
  • 项目类别:
Novel Biomarkers for Post-Liver Transplant NASH Fibrosis
肝移植后 NASH 纤维化的新型生物标志物
  • 批准号:
    10667657
  • 财政年份:
    2022
  • 资助金额:
    $ 60.14万
  • 项目类别:
Biomarkers of Alcoholic Hepatitis
酒精性肝炎的生物标志物
  • 批准号:
    10407997
  • 财政年份:
    2020
  • 资助金额:
    $ 60.14万
  • 项目类别:
Pilot and Feasibility
试点与可行性
  • 批准号:
    10117250
  • 财政年份:
    2019
  • 资助金额:
    $ 60.14万
  • 项目类别:
Pilot and Feasibility
试点与可行性
  • 批准号:
    10372014
  • 财政年份:
    2019
  • 资助金额:
    $ 60.14万
  • 项目类别:
Pilot and Feasibility
试点与可行性
  • 批准号:
    10589770
  • 财政年份:
    2019
  • 资助金额:
    $ 60.14万
  • 项目类别:
Liver-enriched Transcription Factors as Prognostic Markers and Therapeutic Targets in Alcoholic Hepatitis
肝脏富集转录因子作为酒精性肝炎的预后标志物和治疗靶点
  • 批准号:
    10428560
  • 财政年份:
    2018
  • 资助金额:
    $ 60.14万
  • 项目类别:
Pilot Project Core
试点项目核心
  • 批准号:
    8978010
  • 财政年份:
    2016
  • 资助金额:
    $ 60.14万
  • 项目类别:
Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage-diversity supplement
ECM和炎症重塑在酒精性肝肺损伤中的作用-多样性补充
  • 批准号:
    9121282
  • 财政年份:
    2015
  • 资助金额:
    $ 60.14万
  • 项目类别:

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