Targeting HNF4-induced thrombo-inflammation in Chagas disease

Project: Research project

Project Details

Description

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.
StatusActive
Effective start/end date6/15/235/31/25

Funding

  • National Institute of Allergy and Infectious Diseases: $240,000.00

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