Role of miR-222 in pathological hypertrophy and heart failure

miR-222在病理性肥厚和心力衰竭中的作用

基本信息

  • 批准号:
    9250361
  • 负责人:
  • 金额:
    $ 42.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-12-24 至 2020-11-30
  • 项目状态:
    已结题

项目摘要

Pathological hypertrophy is a common predecessor to heart failure (HF). The heart also grows in response to exercise but this growth, termed physiological hypertrophy, does not generally lead to adverse consequences and can even protect the heart against pathological stress. There is a fundamental gap in our understanding of why cardiac hypertrophy can have such divergent outcomes. Our over-arching hypothesis is that there are distinct forms of hypertrophy, which may appear superficially similar but have dramatically different likelihoods of progressing to HF. Our long-term goal is to understand the pathways responsible for these differences and learn whether they can be exploited therapeutically. The objective of the current application is to understand the role of the microRNA (miRNA), miR-222, in pathological hypertrophy and HF. Prior work from the applicant's laboratory identified 16 cardiac miRNAs that were concordantly regulated in two distinct exercise models. Of these, miR-222, which is also increased in serum of HF patients after exercise, was necessary for exercise-induced physiological cardiac growth. While miR-222 was not sufficient to induce cardiac hypertrophy at baseline, it was sufficient to protect against adverse remodeling after ischemic injury. The role of miR-222 in pathological hypertrophy and HF remains unexplored. Based on preliminary data presented in this application, we hypothesize that miR-222 – despite being involved in physiological hypertrophy – paradoxically protects against pathological hypertrophy and the progression to HF. Moreover, we hypothesize that miR-222 acts as a nodal modulator of physiological versus pathological genetic programs at least in part through effects on two transcription factors: HMBOX1 and NFATc3. These central hypotheses will be tested in three integrated Specific Aims. In Aim 1, we will use specific and effective gain- and loss-of-function models to directly assess the role of miR-222 in pathological hypertrophy and HF. In Aim 2, a combination of expression profiling and bioinformatic analyses will be used to identify downstream targets of miR-222 and delineate the mechanisms responsible for its effects in pathological hypertrophy and HF. In Aim 3, a novel technology termed CombiGEM (Combinatorial Genetics En Masse), recently developed by our collaborator, Dr. Tim Lu of the MIT Synthetic Biology group, will be used to investigate the additive or synergistic effects of miRNAs altered in exercised hearts. In vivo studies will be supported by in vitro investigation of primary cardiomyocytes to elucidate the underlying mechanisms. Our approach combines innovative hypotheses, technologies, and unique animal models with the complementary expertise of an outstanding team of collaborating investigators. The proposed research is significant, because it is expected to advance our understanding of cardiac hypertrophy and HF as well as pathways with the potential to mitigate these clinically important conditions.
病理性肥大是心力衰竭(HF)的常见前驱。心也长在 但是这种生长,称为生理性肥大,通常不会导致不良的运动反应。 甚至可以保护心脏免受病理性压力。在我们的社会中, 了解为什么心脏肥大会有如此不同的结果。我们的过度假设 有不同形式的肥大,表面上看起来相似,但 发展成心力衰竭的可能性不同我们的长期目标是了解 这些差异,并了解它们是否可以用于治疗。当前的目标 应用是了解微小RNA(miRNA),miR-222在病理性肥大和HF中的作用。 申请人实验室先前的工作鉴定了16种心脏miRNAs,它们在心肌细胞中一致调节。 两种不同的锻炼模式。其中,miR-222在HF患者的血清中也增加, 运动,是必要的运动诱导的生理心脏生长。虽然miR-222不足以 在基线时诱导心脏肥大,足以防止 缺血性损伤miR-222在病理性肥大和HF中的作用尚未探索。基于 本申请中提供的初步数据,我们假设miR-222 -尽管参与了 生理性肥大-矛盾的是防止病理性肥大和进展, HF。此外,我们假设miR-222作为生理与病理的节点调节剂, 遗传程序至少部分通过影响两个转录因子:HMBOX 1和NFATc 3。这些 将在三个综合具体目标中检验中心假设。在目标1中,我们将使用特定的和 直接评估miR-222在病理性肥大中作用的有效功能获得和丧失模型 和HF。在目标2中,将使用表达谱分析和生物信息学分析的组合来鉴定 miR-222的下游靶点,并描述其在病理学中作用的机制。 肥大和HF。在目标3中,一种称为CombiGEM(组合遗传学混合)的新技术, 最近由我们的合作者,麻省理工学院合成生物学小组的Tim Lu博士开发的,将用于 研究运动心脏中改变的miRNA的相加或协同效应。体内研究将 通过对原代心肌细胞的体外研究来阐明潜在的机制。我们 方法结合了创新的假设,技术和独特的动物模型, 一个优秀的合作调查员团队的专业知识。拟议的研究意义重大, 因为它有望促进我们对心脏肥大和HF以及与HF相关的通路的理解。 缓解这些临床重要状况的潜力。

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 }}

ANTHONY ROSENZWEIG其他文献

ANTHONY ROSENZWEIG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('ANTHONY ROSENZWEIG', 18)}}的其他基金

Understanding the Cardiac Benefits of Exercise at the Cellular and Molecular Level
从细胞和分子水平了解运动对心脏的益处
  • 批准号:
    10322189
  • 财政年份:
    2021
  • 资助金额:
    $ 42.97万
  • 项目类别:
Understanding the Cardiac Benefits of Exercise at the Cellular and Molecular Level
从细胞和分子水平了解运动对心脏的益处
  • 批准号:
    10889616
  • 财政年份:
    2021
  • 资助金额:
    $ 42.97万
  • 项目类别:
Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
  • 批准号:
    10540381
  • 财政年份:
    2019
  • 资助金额:
    $ 42.97万
  • 项目类别:
Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
  • 批准号:
    10319962
  • 财政年份:
    2019
  • 资助金额:
    $ 42.97万
  • 项目类别:
Discovery and characterization of lncRNAs involved in cardiac exercise phenotypes
参与心脏运动表型的 lncRNA 的发现和表征
  • 批准号:
    9885953
  • 财政年份:
    2019
  • 资助金额:
    $ 42.97万
  • 项目类别:
Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
  • 批准号:
    10831299
  • 财政年份:
    2019
  • 资助金额:
    $ 42.97万
  • 项目类别:
Role of Activin Type II receptor signaling in age-related heart failure
激活素 II 型受体信号传导在年龄相关性心力衰竭中的作用
  • 批准号:
    10063936
  • 财政年份:
    2019
  • 资助金额:
    $ 42.97万
  • 项目类别:
Does Exercise Induce Cardiomyogenesis?
运动会诱导心肌生成吗?
  • 批准号:
    8916527
  • 财政年份:
    2014
  • 资助金额:
    $ 42.97万
  • 项目类别:
Does Exercise Induce Cardiomyogenesis?
运动会诱导心肌生成吗?
  • 批准号:
    8699591
  • 财政年份:
    2014
  • 资助金额:
    $ 42.97万
  • 项目类别:
Micro-RNA regulation of the cardiac exercise response
心脏运动反应的微小RNA调节
  • 批准号:
    8606241
  • 财政年份:
    2013
  • 资助金额:
    $ 42.97万
  • 项目类别:

相似海外基金

Contribution of rare genetic variants to aortic valve stenosis in Quebec French-Canadians
罕见遗传变异对魁北克法裔加拿大人主动脉瓣狭窄的影响
  • 批准号:
    493134
  • 财政年份:
    2023
  • 资助金额:
    $ 42.97万
  • 项目类别:
Role of clonal hematopoiesis of indeterminate potential in development of calcific aortic valve stenosis
不确定潜能克隆造血在钙化性主动脉瓣狭窄发展中的作用
  • 批准号:
    23K07522
  • 财政年份:
    2023
  • 资助金额:
    $ 42.97万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Comprehensive exploratory study on aortic valve stenosis with activated macrophages as the main axis
以活化巨噬细胞为主轴的主动脉瓣狭窄综合探索性研究
  • 批准号:
    23K07512
  • 财政年份:
    2023
  • 资助金额:
    $ 42.97万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of an Artificial Intelligence Model for Evaluation of Echocardiographic Severity in Aortic Valve Stenosis
开发用于评估主动脉瓣狭窄超声心动图严重程度的人工智能模型
  • 批准号:
    23K15111
  • 财政年份:
    2023
  • 资助金额:
    $ 42.97万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Imaging Substudy of the BEST Trial: Balloon-Expandable versus Self-expanding Transcatheter Heart Valve for Treatment of Symptomatic Native Aortic Valve Stenosis
最佳试验的影像学子研究:球囊扩张式与自扩张式经导管心脏瓣膜治疗症状性自体主动脉瓣狭窄
  • 批准号:
    460606
  • 财政年份:
    2022
  • 资助金额:
    $ 42.97万
  • 项目类别:
    Operating Grants
Using Claims-Based Signatures of Frailty to Support Individualized Treatment of Aortic Valve Stenosis and Coronary Artery Disease
使用基于索赔的虚弱特征来支持主动脉瓣狭窄和冠状动脉疾病的个体化治疗
  • 批准号:
    10363612
  • 财政年份:
    2020
  • 资助金额:
    $ 42.97万
  • 项目类别:
Using Claims-Based Signatures of Frailty to Support Individualized Treatment of Aortic Valve Stenosis and Coronary Artery Disease
使用基于索赔的虚弱特征来支持主动脉瓣狭窄和冠状动脉疾病的个体化治疗
  • 批准号:
    10545062
  • 财政年份:
    2020
  • 资助金额:
    $ 42.97万
  • 项目类别:
Investigating the role of CaV1.2 in aortic valve stenosis
研究 CaV1.2 在主动脉瓣狭窄中的作用
  • 批准号:
    10421276
  • 财政年份:
    2020
  • 资助金额:
    $ 42.97万
  • 项目类别:
Investigating the role of CaV1.2 in aortic valve stenosis
研究 CaV1.2 在主动脉瓣狭窄中的作用
  • 批准号:
    10132390
  • 财政年份:
    2020
  • 资助金额:
    $ 42.97万
  • 项目类别:
Investigating the role of CaV1.2 in aortic valve stenosis
研究 CaV1.2 在主动脉瓣狭窄中的作用
  • 批准号:
    10611495
  • 财政年份:
    2020
  • 资助金额:
    $ 42.97万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了