Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure
mRNA结合蛋白tristetraprolin在心脏mRNA调节和心力衰竭发展中的作用
基本信息
- 批准号:10544156
- 负责人:
- 金额:$ 57.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-15 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAcidsAddressAmino AcidsAnimal ModelBindingBinding ProteinsBranched-Chain Amino AcidsCardiacCardiac MyocytesCatabolismCell physiologyClinicalCo-ImmunoprecipitationsCollaborationsComplexDataDefectDeveloped CountriesDevelopmentDiseaseElementsEpidemicFatty AcidsGenesGenetic studyHealthHeartHeart failureHomeostasisHumanImpairmentInflammationInflammatoryInsulinIschemiaKeto AcidsKnock-outKnockout MiceKnowledgeLinkLipidsMeasuresMediatingMessenger RNAMetabolic syndromeMetabolismModelingMusOxidoreductasePPAR alphaPathologyPathway interactionsPerfusionPharmaceutical PreparationsProcessProtein phosphataseProteinsRNARegulationRoleStressSystemTIS11 proteinTNF geneTestingTissuesZinc Fingersamino acid metabolismaorta constrictionbranched chain alpha ketoacid dehydrogenasebranched chain fatty acidclinically relevantdrug discoveryfatty acid metabolismfatty acid oxidationheart functionheart metabolismheart preservationimprovedinduced pluripotent stem cellknock-downlipid metabolismmRNA Transcript Degradationnew therapeutic targetnoveloxidationposttranscriptionalpreservationpressureresponseside effectsystemic inflammatory responseuptake
项目摘要
Heart failure (HF) is a major health epidemic in developed countries, however, its underlying pathology is not
well characterized. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to AU-rich elements (ARE) in
the 3’-untranslated region (UTR) of target mRNA molecules, and induces their degradation. Global TTP knockout
(KO) mice display systemic inflammation, since TNFα mRNA is normally degraded by TTP, and deletion of TTP
leads to elevated TNFα levels. Thus, very few studies have assessed the role of TTP in metabolism despite its
original discovery as an insulin-inducible gene, and genetic studies linking TTP to metabolic syndrome. We are
addressing this fundamental gap in knowledge, and our strong preliminary data suggest critical activities by TTP
in cardiac metabolism and the development of HF. Specifically, we have shown that TTP inhibits fatty acid (FA)
and branched-chain amino acid (BCAA) metabolism (independent of its effects on inflammation), and reduces
the mRNA levels of key proteins in these processes, i.e., peroxisome proliferator-activated receptor (PPAR)-α
and branched-chain α–ketoacid acid dehydrogenase complex (BCKDC)-E2 subunits. The central hypothesis
of this proposal is that TTP inhibits cardiac FA and BCAA metabolism by binding to and degrading
PPARα and BCKDC-E2 mRNAs, and that TTP exacerbates the development of HF by impairing FA and
BCAA metabolism. In Aim 1, we will assess whether TTP inhibits cardiac FA metabolism by binding to PPARα
mRNA and promoting its degradation. We will assess whether TTP binds to PPARα mRNA by performing RNA
co-immunopreciptation (co-IP) and deletion studies of PPARα 3’-UTR AREs. We will also measure FA uptake
and metabolism in the hearts from cardiac-specific TTP KO (csTTP-KO) mice, and will determine whether these
changes are through PPARα using TTP/PPARα double KO mice. In Aim 2, we will determine whether TTP
decreases BCAA catabolism through binding and degradation of BCKDC-E2 mRNA. We will first determine
whether TTP binds BCKDC-E2 mRNA by performing RNA co-IP and deletion studies on BCKDC-E2 3’-UTR
AREs. We will also measure BCAA levels and BCKDC activity in heart tissue from csTTP-KO mice. To
demonstrate whether the reduction in BCAA catabolism with TTP KO is through BCKDC-E2, we will perform
similar studies with knockdown of TTP and BCKDC-E2. In Aim 3, we will determine whether TTP has detrimental
effects on the heart under stress conditions, and whether this depends upon impaired FA and BCAA metabolism.
We will subject csTTP-KO mice to pressure overload and ischemia, then assess their cardiac function and
metabolism. To determine the role of PPARα and BCKDC in this process, we will use csTTP/PPARα double KO
mice and will cross csTTP-KO with protein phosphatase 2Cm KO mice (which have reduced BCKDC activity),
and assess cardiac response to stress. We will also show our studies to develop novel drugs that target TTP
without inducing inflammation, providing potential clinical implications for Aim 3. These studies will improve our
understanding of cardiac metabolism, and may lead to new avenues for treatment of HF.
心衰(HF)在发达国家是一种主要的健康流行病,然而,其潜在的病理却不是
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 }}
Hossein Ardehali其他文献
Hossein Ardehali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('Hossein Ardehali', 18)}}的其他基金
Role of mRNA-binding protein tristetraprolin in cardiac mRNA regulation and the development of heart failure
mRNA结合蛋白tristetraprolin在心脏mRNA调节和心力衰竭发展中的作用
- 批准号:
10365412 - 财政年份:2021
- 资助金额:
$ 57.76万 - 项目类别:
Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells
使用人类诱导多能干细胞深入了解线粒体铁在阿霉素诱导的心肌病中的作用
- 批准号:
10577780 - 财政年份:2020
- 资助金额:
$ 57.76万 - 项目类别:
Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells
使用人类诱导多能干细胞深入了解线粒体铁在阿霉素诱导的心肌病中的作用
- 批准号:
10352437 - 财政年份:2020
- 资助金额:
$ 57.76万 - 项目类别:
Mechanistic insights into the role of mitochondrial iron in doxorubicin-induced cardiomyopathy using human induced pluripotent stem cells
使用人类诱导多能干细胞深入了解线粒体铁在阿霉素诱导的心肌病中的作用
- 批准号:
9916208 - 财政年份:2020
- 资助金额:
$ 57.76万 - 项目类别:
Mechanistic insights into HIV-mediated heart failure with preserved ejection fraction
HIV介导的射血分数保留的心力衰竭的机制见解
- 批准号:
9476609 - 财政年份:2018
- 资助金额:
$ 57.76万 - 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
- 批准号:
10216328 - 财政年份:2018
- 资助金额:
$ 57.76万 - 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
- 批准号:
10432041 - 财政年份:2018
- 资助金额:
$ 57.76万 - 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
- 批准号:
9761573 - 财政年份:2018
- 资助金额:
$ 57.76万 - 项目类别:
Third Coast HIV-Related Cardiovascular and Sleep Disorders K12 Career Development Program
第三海岸 HIV 相关心血管和睡眠障碍 K12 职业发展计划
- 批准号:
9614669 - 财政年份:2018
- 资助金额:
$ 57.76万 - 项目类别:
Northwestern University Molecular and Translational Cardiovascular Training Program
西北大学分子与转化心血管培训项目
- 批准号:
9358906 - 财政年份:2017
- 资助金额:
$ 57.76万 - 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:
$ 57.76万 - 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:
$ 57.76万 - 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:
$ 57.76万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 57.76万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 57.76万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 57.76万 - 项目类别:
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:
$ 57.76万 - 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:
$ 57.76万 - 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:
$ 57.76万 - 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:
$ 57.76万 - 项目类别: