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

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)
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Hossein Ardehali其他文献

Hossein Ardehali的其他文献

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{{ 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:

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