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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

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.

项目摘要由克氏锥虫（Tc）引起的恰加斯病（CD）是墨西哥最高的寄生虫病负担，西半球查加斯病患者血栓栓塞事件和中风的发生率很高，每年造成约7000人死亡。由于医疗保健，CD的经济负担估计约为100亿美元成本和过早死亡造成的生产力损失，并为投资于开发CD的新疗法。人类研究和我们在实验模型中的初步数据显示在CD的早期阶段凝血因子（CF）表达和活化增加，在临床症状性心脏病和缺血性中风发生率变得临床明显之前。肝细胞核因子4 β（HNF 4 β）调节CFs基因表达，我们发现Tc诱导的DAMPs 表明HNF 4（HNF 1成人和HNF 3胎儿同种型）表达和转录活性在肝脏中增加， CD.公开可用的ChIP-seq数据集和我们的初步结果表明，HNF 4可能会影响组装核蛋白复合物和DNA-组蛋白表观遗传标记调控CFs基因表情因此，在这个项目中，我们将测试的假设，Tc和Tc诱导DAMPs失调在基因表达和激活水平上进行凝血止血，并使HNF 4 β 1/β 3水平正常化将稳定促凝血剂-抗凝剂动力学并限制血栓前和致病事件， CD.使用我们的小鼠感染模型和原代和培养的肝细胞，工具，我们将测试我们的假设在两个目标。在目标1中，我们将评估CF的纵向变化在CD发展过程中的表达、活化和血栓形成;并检查在CD发展过程中是否进行治疗。用抗寄生虫药物或分子诱饵使HNF 4 β 1/β 3水平正常化可预防Chagglutinin小鼠脑和心脏的高凝状态和血管血栓，从而控制 CD发病机制。在目标2中，我们将从分子水平上观察到， CD期间HNF 4亚型和核心DNA核蛋白的活性，并研究HNF 4如何与CD相互作用靶基因启动子上的核蛋白和组蛋白表观遗传标记影响CFs的肝脏表达在CD中。我们相信这些研究将为HNF 4 β缺陷如何导致血友病提供新的见解并可能导致新的治疗策略（例如，反义寡核苷酸纠正HNF 4亚型），控制恰加斯病和其他心脏和神经系统疾病，其中血栓形成倾向是一个关键的病因因素。