Targeting HNF4-induced thrombo-inflammation in Chagas disease

针对恰加斯病中 HNF4 诱导的血栓炎症

• 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
• 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' 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

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 查加斯病(CD)是由克氏锥虫(Tc)引起的 西半球。Chagas患者经历血栓栓子事件和中风的高发生率 每年造成约7000人死亡。CD的经济负担估计约为100亿美元，原因是医疗保健 成本和过早死亡造成的生产力损失，这为投资于 CD新疗法的开发。人体研究和我们在实验模型中的初步数据 提示CD早期凝血因子(CFs)表达和活化增强， 在有临床症状的心脏病和缺血性中风的发病率变得临床明显之前。 肝细胞核因子4(HNF4)调节CFs基因的表达，我们发现TC诱导的抑制 肝脏中HNF4(1成体和3胎儿亚型)表达和转录活性增加的信号 CD.公开可用的CHIP-SEQ数据集和我们的初步结果表明，HNF4可能会影响 组装核蛋白复合体和DNA-组蛋白表观遗传标志调控CFS基因 表情。因此，在这个项目中，我们将检验这样一种假设，即TC和TC诱导的阻尼器失调 在基因表达和激活水平上的凝血止血，并使HNF41/3水平正常化 将稳定促凝剂-抗凝剂的动态，并限制血栓前事件和致病事件 CD.利用我们的小鼠感染模型和具有尖端分子的原代和培养的肝细胞 工具，我们将在两个目标上检验我们的假设。在目标1中，我们将评估CFS的纵向变化 CD发展过程中的表达、激活和血栓形成；并检查在CD发展过程中的治疗是否 用抗寄生虫药物或分子诱饵使HNF41/3水平正常化的不确定到慢性期 能预防失调症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，我们将获得表达、分布和变化的分子视图。 CD过程中HNF4DNA异构体和核心核蛋白的活性以及HNF4与 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HNF4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HNF4亚型) 控制查加斯和其他心脏和神经疾病，其中血栓形成是一个关键的病因因素。