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:
- 金额:$ 24万
- 依托单位:
- 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:
- 关键词:5&apos Untranslated RegionsAbbreviationsAcetylationAcuteAddressAdultAffectAffinityAndrostanesAntibodiesAnticoagulantsAntigen-Presenting CellsAntisense OligonucleotidesAttentionBenznidazoleBindingBlood Coagulation DisordersBlood Coagulation FactorBlood PlateletsBlood VesselsBlood coagulationBlood flowBrainCardiomyopathiesCerebrovascular DisordersCessation of lifeChIP-seqChagas DiseaseChronicChronic PhaseClinicalCoagulation Factor GeneCoagulation ProcessCommunicable DiseasesComplexConditioned Culture MediaCyclic GMPDNADNA PackagingDataData SetDefectDevelopmentDiseaseEconomic BurdenEndothelial CellsEpigenetic ProcessEtiologyEventExonsExperimental ModelsExposure toFibrinFibrinogenFrequenciesGene ActivationGene ExpressionGenesGenetic TranscriptionGlobinGoalsHNF4A geneHealthHealth Care CostsHeartHeart DiseasesHemophilia AHemostatic AgentsHemostatic functionHepaticHepatocyteHeterodimerizationHistonesHomoHumanIn VitroIncidenceInfectionInflammatoryInvestmentsIschemic StrokeLeft ventricular structureLiteratureLiverLysineMacrophageMammalsMethylationMolecularMusMyocardial IschemiaNeuraminidaseNucleoproteinsOutcomePF4 GeneParasitesParasitic DiseasesPathogenesisPathogenicityPatientsPatternPeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPhasePlasmaPlatelet ActivationProcessProductivityPromoter RegionsProtein CProtein IsoformsProtein SProteinsProthrombinRNA SplicingReactive Oxygen SpeciesRecurrenceRegulationResearch PersonnelRoleSignal TransductionSiteStressStrokeTestingThromboembolismThrombophiliaThromboplastinThromboxanesThrombusTissuesTranscriptional ActivationTranscriptional RegulationTrypanosoma cruziUntranslated RegionsVariantWestern Blottingadaptive immunityburden of illnesschromatin immunoprecipitationepigenomeexperienceextracellular vesiclesfetalhepatocyte nuclear factorin vivo Modelinsightmortality riskmouse modelnervous system disordernovelnovel therapeutic interventionnovel therapeuticsplasma protein Zpregnane X receptorprematurepreventpromoterrecruitstroke incidencethrombogenesisthromboinflammationtooltranscription factorvascular 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 HNF41/3 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 HNF41/3 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HNF41/3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HNF41/3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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nisha Jain Garg其他文献
NADPH Oxidase: Role in Progression of Myocarditis During Trypanosoma cruzi Infection and Chagas Disease
- DOI:
10.1016/j.freeradbiomed.2010.10.393 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Nisha Jain Garg;Monisha Dhiman - 通讯作者:
Monisha Dhiman
Nisha Jain Garg的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nisha Jain Garg', 18)}}的其他基金
Mitochondrial Biomarkers of Cardiomyopathy and Cure in Chagas Disease
心肌病的线粒体生物标志物和恰加斯病的治疗
- 批准号:
8666721 - 财政年份:2013
- 资助金额:
$ 24万 - 项目类别:
Mitochondrial Biomarkers of Cardiomyopathy and Cure in Chagas Disease
心肌病的线粒体生物标志物和恰加斯病的治疗
- 批准号:
8568036 - 财政年份:2013
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
7994825 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
7567886 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
8210908 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
9751200 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
9571194 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
10219916 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Oxidative Response Networks in Chagasic Cardiomyopathy
恰加斯心肌病的氧化反应网络
- 批准号:
7752870 - 财政年份:2009
- 资助金额:
$ 24万 - 项目类别:
Human serum carbonyl proteome in cardiovascular diseases
心血管疾病中的人血清羰基蛋白质组
- 批准号:
7530425 - 财政年份:2008
- 资助金额:
$ 24万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 24万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 24万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 24万 - 项目类别:
Research Grant
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 24万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 24万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 24万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 24万 - 项目类别: