Targeting HNF4-induced thrombo-inflammation in Chagas disease

针对恰加斯病中 HNF4 诱导的血栓炎症

基本信息

批准号：
10727268
负责人：
Nisha Jain Garg
金额：
$ 24万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727268
关键词：
5&apos Untranslated Regions Abbreviations Acetylation Acute Address Adult Affect Affinity Androstanes Antibodies Anticoagulants Antigen-Presenting Cells Antisense Oligonucleotides Attention Benznidazole Binding Blood Coagulation Disorders Blood Coagulation Factor Blood Platelets Blood Vessels Blood coagulation Blood flow Brain Cardiomyopathies Cerebrovascular Disorders Cessation of life ChIP-seq Chagas Disease Chronic Chronic Phase Clinical Coagulation Factor Gene Coagulation Process Communicable Diseases Complex Conditioned Culture Media Cyclic GMP DNA DNA Packaging Data Data Set Defect Development Disease Economic Burden Endothelial Cells Epigenetic Process Etiology Event Exons Experimental Models Exposure to Fibrin Fibrinogen Frequencies Gene Activation Gene Expression Genes Genetic Transcription Globin Goals HNF4A gene Health Health Care Costs Heart Heart Diseases Hemophilia A Hemostatic Agents Hemostatic function Hepatic Hepatocyte Heterodimerization Histones Homo Human In Vitro Incidence Infection Inflammatory Investments Ischemic Stroke Left ventricular structure Literature Liver Lysine Macrophage Mammals Methylation Molecular Mus Myocardial Ischemia Neuraminidase Nucleoproteins Outcome PF4 Gene Parasites Parasitic Diseases Pathogenesis Pathogenicity Patients Pattern Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Plasma Platelet Activation Process Productivity Promoter Regions Protein C Protein Isoforms Protein S Proteins Prothrombin RNA Splicing Reactive Oxygen Species Recurrence Regulation Research Personnel Role Signal Transduction Site Stress Stroke Testing Thromboembolism Thrombophilia Thromboplastin Thromboxanes Thrombus Tissues Transcriptional Activation Transcriptional Regulation Trypanosoma cruzi Untranslated Regions Variant Western Blotting adaptive immunity burden of illness chromatin immunoprecipitation epigenome experience extracellular vesicles fetal hepatocyte nuclear factor in vivo Model insight mortality risk mouse model nervous system disorder novel novel therapeutic intervention novel therapeutics plasma protein Z pregnane X receptor premature prevent promoter recruit stroke incidence thrombogenesis thromboinflammation tool transcription factor vascular injury

5&apos Untranslated Regions Abbreviations Acetylation Acute Address Adult Affect Affinity Androstanes Antibodies Anticoagulants Antigen-Presenting Cells Antisense Oligonucleotides Attention Benznidazole Binding Blood Coagulation Disorders Blood Coagulation Factor Blood Platelets Blood Vessels Blood coagulation Blood flow Brain Cardiomyopathies Cerebrovascular Disorders Cessation of life ChIP-seq Chagas Disease Chronic Chronic Phase Clinical Coagulation Factor Gene Coagulation Process Communicable Diseases Complex Conditioned Culture Media Cyclic GMP DNA DNA Packaging Data Data Set Defect Development Disease Economic Burden Endothelial Cells Epigenetic Process Etiology Event Exons Experimental Models Exposure to Fibrin Fibrinogen Frequencies Gene Activation Gene Expression Genes Genetic Transcription Globin Goals HNF4A gene Health Health Care Costs Heart Heart Diseases Hemophilia A Hemostatic Agents Hemostatic function Hepatic Hepatocyte Heterodimerization Histones Homo Human In Vitro Incidence Infection Inflammatory Investments Ischemic Stroke Left ventricular structure Literature Liver Lysine Macrophage Mammals Methylation Molecular Mus Myocardial Ischemia Neuraminidase Nucleoproteins Outcome PF4 Gene Parasites Parasitic Diseases Pathogenesis Pathogenicity Patients Pattern Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Plasma Platelet Activation Process Productivity Promoter Regions Protein C Protein Isoforms Protein S Proteins Prothrombin RNA Splicing Reactive Oxygen Species Recurrence Regulation Research Personnel Role Signal Transduction Site Stress Stroke Testing Thromboembolism Thrombophilia Thromboplastin Thromboxanes Thrombus Tissues Transcriptional Activation Transcriptional Regulation Trypanosoma cruzi Untranslated Regions Variant Western Blotting adaptive immunity burden of illness chromatin immunoprecipitation epigenome experience extracellular vesicles fetal hepatocyte nuclear factor in vivo Model insight mortality risk mouse model nervous system disorder novel novel therapeutic intervention novel therapeutics plasma protein Z pregnane X receptor premature prevent promoter recruit stroke incidence thrombogenesis thromboinflammation tool transcription factor vascular injury

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项目摘要

Project Summary Chagas disease (CD), caused by Trypanosoma cruzi (Tc), represents the highest parasitic disease burden in Western hemisphere. Chagas patients experience high incidences of thromboembolic events and stroke that result in ~7000 deaths every year. The economic burden of CD is estimated at ~$10 billion due to healthcare costs and lost productivity by premature deaths, and it provides a strong rationale for investment in the development of new therapies for CD. Studies in humans and our preliminary data in experimental models show that coagulation factors (CFs) expression and activation were increased during early phases of CD, before the clinically symptomatic cardiac disease and ischemic stroke incidences become clinically apparent. Hepatocyte nuclear factor 4 (HNF4) regulates CFs gene expression, and we found that Tc-induced DAMPs signal a hepatic increase in HNF4 (1 adult and 3 fetal isoforms) expression and transcriptional activity in CD. Publicly available ChIP-seq datasets and our preliminary results suggest that HNF4 may influence the assembly of the nucleoproteins complex and DNA-histones epigenetic signature to regulate CFs gene expression. Thus, in this project, we will test the hypothesis that Tc and Tc-induced DAMPs dysregulate coagulation hemostasis at the gene expression and activation levels, and normalizing the HNF41/3 levels will stabilize the procoagulants - anticoagulants dynamics and limit the prothrombotic and pathogenic events in CD. Using our mouse model of infection and primary and cultured hepatocytes with cutting-edge molecular tools, we will test our hypothesis in two aims. In aim 1, we will evaluate the longitudinal changes in CFs expression, activation, and thrombogenesis during CD development; and examine if treatment during the indeterminate-to-chronic phase with anti-parasite drug or molecular decoys to normalize HNF41/3 levels would prevent hypercoagulability and vascular thrombi in brain and heart of chagasic mice, thereby controlling CD pathogenesis. In aim 2, we will obtain a molecular view of the changes in the expression, distribution, and activity of HNF4 isoforms and core DNA nucleoproteins during CD and examine how HNF4 interactions with nucleoproteins and histone epigenetic marks on target gene promoters influence the hepatic expression of CFs in CD. We believe these studies will provide novel insights into how HNF4 defects contribute to hemophilia and may lead to novel therapeutic strategies (eg, antisense oligonucleotides to correct HNF4 isoforms) to control Chagas and other cardiac and neurological disorders in which thrombophilia is a key etiologic factor.

项目摘要由克鲁齐锥虫（TC）引起的Chagas病（CD）代表了寄生虫伯恩的最高西半球。查加斯患者经历了血栓栓塞事件的高分子和中风每年导致约7000人死亡。由于医疗保健，CD的经济燃烧估计约为100亿美元成本和因过早死亡而失去生产力，它为投资提供了强有力的理由开发CD的新疗法。人类研究和我们的初步数据表明在CD的早期阶段，凝血因子（CFS）表达和激活增加，在临床上有症状性心脏病和缺血性卒中疾病之前，在临床上显而易见。肝细胞核因子4（HNF4）调节CFS基因表达，我们发现TC诱导的潮湿在HNF4（1成人和fet胎胎同工型）表达和转录活性的HNF4（1成人和1）中的肝素增加光盘。公开可用的芯片序列数据集和我们的初步结果表明，HNF4可能会影响核蛋白复合物的组装和DNA-histones表观遗传学特征来调节CFS基因表达。在这个项目中，我们将检验以下假设，即TC和TC诱导的潮湿失调在基因表达和激活水平上凝血止血，并使HNF41/3水平归一化将稳定Procagulans-抗凝剂动力学，并限制促血栓形成和致病事件光盘。使用我们的小鼠感染模型以及尖端分子的原发性和培养的肝细胞工具，我们将以两个目的测试我们的假设。在AIM 1中，我们将评估CFS的纵向变化 CD发育过程中的表达，激活和血栓形成；并检查是否在抗寄生虫药物或分子诱饵的不确定阶段，以归一化HNF41/3水平会防止大脑和心脏的chagasic小鼠的高凝性和血管血栓，从而控制 CD发病机理。在AIM 2中，我们将获得表达，分布和分布变化的分子视图 CD期间HNF4同工型和核心DNA核蛋白的活性，并检查HNF4如何与靶基因启动子上的核蛋白和Hisstone表观遗传标记会影响CFS的肝表达在CD中。我们认为，这些研究将提供有关HNF4缺陷如何有助于血友病的新见解。并可能导致新的治疗策略（例如，反义寡核苷酸以校正HNF4同工型）控制血栓形成是关键的病因因素，控制chagas和其他心脏和神经系统疾病。