Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis

地高辛抑制酒精性肝炎无菌性炎症

基本信息

批准号：
9791135
负责人：
WAJAHAT Zafar MEHAL
金额：
$ 24.56万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9791135
关键词：
Affinity Alcohol consumption Alcoholic Hepatitis Alcohols Aptamer Technology Bacteremia Binding Cardiac Glycosides Clinical Clinical Data Clinical Trials Complement Complication DNA Data Development Digoxin Dose Early identification Enzymes Ethanol Fibroblast Growth Factor Gene Proteins Gene Targeting Genes Grant Health Heavy Drinking Hepatocyte Human Hypoxia Immune Inflammation Inflammatory Inflammatory Response Inpatients Kininogenase Laboratory Markers Ligands Liver Liver diseases Mitochondrial DNA Modeling Molecular Nuclear Oral Oxides Pathway interactions Patients Pharmaceutical Preparations Plasma Proteins Proteomics Pyruvate Kinase Reactive Oxygen Species Response Elements Sepsis Serum Signal Transduction Sterility Sustainable Development TNF gene Testing Therapeutic Therapeutic Intervention Therapeutic Uses Tissues Up-Regulation White Blood Cell Count procedure Work alcohol measurement aptamer base cohort effective therapy gamma-Chain Immunoglobulins healthy volunteer high throughput screening liver inflammation liver injury molecular marker monocyte mortality novel outcome forecast peripheral blood prognostic tool promoter protein biomarkers receptor response targeted treatment

项目摘要

ABSTRACT: Alcoholic hepatitis (AH) is a major liver disease, and has an inpatient mortality of between 25-40%. Liver inflammation is a key feature of AH, yet the factors which drive this inflammatory response are not known. We have identified novel key drivers of liver inflammation which are the subject of this application. We have also identified novel proteomic and molecular markers in AH which will be used to predict prognosis. We have shown that activation of the nuclear (hypoxia inhibitory factor 1-: HIF-1) pathway was required for the development of sustained sterile inflammation, which suggested that inhibition of HIF-1 may be therapeutic in AH[1]. In a high throughput screen cardiac glycoside were identified to have significant ability to inhibit HIF-1[2]. The preliminary data demonstrates i) Up-regulation of HIF-1 dependent genes in liver tissues from early AH, as compared to severe AH, from the InTeam consortium ii) Ability of digoxin to reduce tissue damage in a model of alcohol, and others forms of liver injury. iii) Digoxin binds to the enzyme pyruvate kinase M2 (PKM2), iv) Digoxin reduces PKM2 binding to the HIF-1 promoter and limits up-regulation of HIF-1, and HIF-1 response genes. v) An aptamer based proteomic analysis of serum shows that in patients with the AH and the systemic inflammatory response (SIRS) there is an increase in tumor necrosis factor related proteins, low affinity immunoglobulin gamma Fc region receptor II, complement components, kallikrein and fibroblast growth factors. vi) Serum DNA is known to be a pro-inflammatory ligand and serum DNA levels correlated with peripheral blood white cell count in AH. Aim 1. Obtain clinical data supporting the therapeutic use of digoxin in alcoholic hepatitis. Aim 2. Identify dominant and novel targets that are regulated by PKM2 in alcoholic hepatitis. Aim 3. Obtain plasma proteomic and molecular data to allow for early identification of patients with SIRS. Collectively this will allow us to obtain the necessary data towards clinically testing low dose digoxin in AH. In addition, it will allow us to identify novel protein markers and pro-inflammatory signals in the serum of patients with AH. Finally, we will be able to identify if any of the novel protein markers are associated with the novel PKM2 pathway we have identified.

摘要：酒精性肝炎（AH）是一种主要的肝脏疾病，住院患者死亡率为 25-40%。肝脏炎症是 AH 的一个关键特征，但驱动这种炎症反应的因素尚不清楚。我们已经确定了肝脏炎症的新关键驱动因素，这也是本申请的主题。鉴定出 AH 中新的蛋白质组和分子标记，可用于预测预后。我们已经证明，需要激活核（缺氧抑制因子 1-α：HIF-1α）途径持续无菌性炎症的发展，这表明抑制 HIF-1α 可能是在高通量筛选中，强心苷被鉴定为具有显着的治疗 AH 的能力。抑制 HIF-1α[2]。初步数据表明 i) 肝组织中 HIF-1α 依赖性基因的上调。早期 AH 与严重 AH 相比，来自 InTeam 联盟 ii) 地高辛减少组织的能力 iii) 地高辛与丙酮酸激酶结合 M2 (PKM2), iv) 地高辛减少 PKM2 与 HIF-1α 启动子的结合并限制 HIF-1α 的上调，以及 v) 基于适体的血清蛋白质组学分析显示，在 AH 患者中，HIF-1α 反应基因。和全身炎症反应（SIRS），肿瘤坏死因子相关蛋白增加，低亲和力免疫球蛋白 γ Fc 区受体 II、补体成分、激肽释放酶和成纤维细胞 vi) 已知血清 DNA 是一种促炎配体，血清 DNA 水平与 AH 中外周血白细胞计数。目标 1. 获得支持地高辛治疗酒精性肝炎的临床数据。目标 2. 确定酒精性肝炎中 PKM2 调节的主要和新靶标。目标 3. 获取血浆蛋白质组和分子数据，以便及早识别 SIRS 患者。总的来说，这将使我们能够获得在 AH 中进行低剂量地高辛临床测试所需的数据。此外，它将使我们能够识别患者血清中的新型蛋白质标记物和促炎信号最后，我们将能够确定是否有任何新的蛋白质标记与新的 PKM2 相关。我们已确定的途径。