Small molecule therapies targeting chromatin architecture in heart failure

针对心力衰竭染色质结构的小分子疗法

基本信息

  • 批准号:
    10534162
  • 负责人:
  • 金额:
    $ 72.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-15 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Distinct transcriptomes in the heart’s different cell types enable adaptation in response to healthy physiological demand and pathologic stress. Epigenomic machinery establishes the nuclear microenvironment for such tailored gene regulation, shutting some genes off and turning others on, in a cell type-specific and stimulus-responsive manner. However, the manner in which epigenomic remodeling underpins cardiac hypertrophy and fibrosis and the spectrum of heart failure phenotypes observed clinically, including with reduced ejection fraction (HFrEF; systolic dysfunction) or preserved EF (HFpEF; diastolic dysfunction), is unknown. Novel classes of epigenetic drugs like HDAC and BET-bromodomain inhibitor (i.e. agents that inhibit chromatin readers) have shown great promise in preclinical studies of heart failure, and are now in a phase III clinical trial to treat atherosclerosis, underscoring the tolerance of these drugs in humans and the potential of developing epigenetic therapies to treat cardiovascular diseases. Further evidence that heart failure is associated with a new, semi-stable and disease-promoting structural environment has come from genome occupancy studies (using ChIP-seq), chromatin conformation capture studies, and analysis of DNA methylation. These findings suggest that if the right subset of genomic loci could be targeted with designer drugs, a new class of epigenomic therapies for the spectrum of heart failure might emerge. This multi-PI application is focused on pharmacologic manipulation of chromatin to identify novel targets for the spectrum of heart failure. To unpack the role of different cell types, we will study epigenomic control in myocytes and fibroblasts, examining distinct models of heart failure, including that resulting from salt, renal dysfunction and hormonal imbalance (unilateral nephrectomized mice with a DOCA pellet and high salt) and mice subjected to pressure overload by transverse aortic constriction, models of heart failure with preserved and reduced ejection fraction, respectively. We hypothesize that epigenetic therapies targeting the intermediate phenotypes of chromatin structure and accessibility afford a powerful opportunity to regulate entire gene expression programs in a therapeutic manner to treat heart failure. Our experiments will characterize chromatin structural changes in different cell types in models of systolic and diastolic dysfunction. We will conclusively investigate the ability of small molecule epigenetic inhibitors to reverse disease-associated phenotypic and chromatin architectural changes in animal models. Lastly, we will determine the mechanisms by which the chromatin eraser family of HDACs and the chromatin reader BRD4 interact to regulate epigenomic architecture and myocyte or fibroblast phenotype. Together, these investigations will validate a complementary class of heart failure therapies in a cell type-specific manner, revealing the changes in chromatin accessibility and structure that underpin pathologic gene expression in clinically distinct forms of heart failure.
项目总结/摘要 心脏不同细胞类型中的不同转录组使其能够适应健康 生理需求和病理应激。表观基因组机制建立核微环境 对于这种定制的基因调控,关闭一些基因并打开其他基因,在特定的细胞类型中, 刺激反应的方式。然而,表观基因组重塑支持心脏的方式, 肥大和纤维化以及临床观察到的心力衰竭表型谱,包括减少的 射血分数(HFrEF;收缩功能障碍)或保留EF(HFpEF;舒张功能障碍)未知。 新型表观遗传药物如HDAC和BET-布罗莫结构域抑制剂(即抑制肿瘤的药剂) 染色质阅读器)在心力衰竭的临床前研究中表现出巨大的希望,目前正处于III期 治疗动脉粥样硬化的临床试验,强调了这些药物在人类中的耐受性和 开发表观遗传疗法来治疗心血管疾病。进一步的证据表明心力衰竭 与一个新的、半稳定的和促进疾病的结构环境相关的基因来自基因组 占据研究(使用ChIP-seq)、染色质构象捕获研究和DNA甲基化分析。 这些发现表明,如果基因组位点的正确子集可以被设计药物靶向, 表观基因组疗法治疗心力衰竭的可能出现。 这种多PI应用程序的重点是染色质的药理学操作,以确定新的目标 心力衰竭的范围。为了揭示不同细胞类型的作用,我们将研究表观基因组控制, 心肌细胞和成纤维细胞,检查不同的心力衰竭模型,包括由盐,肾 功能障碍和激素失衡(DOCA颗粒和高盐的单侧肾切除小鼠), 通过横向主动脉收缩使小鼠经受压力超负荷,用保存的和 射血分数分别降低。我们假设,针对中间体的表观遗传疗法 染色质结构和可接近性的表型为调节整个基因提供了强大的机会 以治疗方式进行表达编程以治疗心力衰竭。我们的实验将描述染色质 收缩和舒张功能障碍模型中不同细胞类型的结构变化。我们将最终 研究小分子表观遗传抑制剂逆转疾病相关表型和 动物模型中染色质结构的变化。最后,我们将确定 HDAC的染色质擦除器家族和染色质阅读器BRD 4相互作用以调节表观基因组结构 和肌细胞或成纤维细胞表型。总之,这些研究将证实一种互补的心脏 以细胞类型特异性方式进行失败治疗,揭示染色质可及性和结构的变化 在临床上不同形式的心力衰竭中支持病理基因表达。

项目成果

期刊论文数量(15)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis.
  • DOI:
    10.1016/j.yjmcc.2020.12.005
  • 发表时间:
    2021-04
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Riching AS;Danis E;Zhao Y;Cao Y;Chi C;Bagchi RA;Klein BJ;Xu H;Kutateladze TG;McKinsey TA;Buttrick PM;Song K
  • 通讯作者:
    Song K
Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia-reperfusion acute kidney injury.
  • DOI:
    10.1038/s41598-021-04701-x
  • 发表时间:
    2022-01-12
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Soranno DE;Baker P 2nd;Kirkbride-Romeo L;Wennersten SA;Ding K;Keith B;Cavasin MA;Altmann C;Bagchi RA;Haefner KR;Montford J;Gist KM;Vergnes L;Reue K;He Z;Elajaili H;Okamura K;Nozik E;McKinsey TA;Faubel S
  • 通讯作者:
    Faubel S
Early adaptive chromatin remodeling events precede pathologic phenotypes and are reinforced in the failing heart.
  • DOI:
    10.1016/j.yjmcc.2021.07.002
  • 发表时间:
    2021-11
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Chapski, Douglas J.;Cabaj, Maximilian;Morselli, Marco;Mason, Rosibel J.;Soehalim, Elizabeth;Ren, Shuxun;Pellegrini, Matteo;Wang, Yibin;Vondriska, Thomas M.;Rosa-Garrido, Manuel
  • 通讯作者:
    Rosa-Garrido, Manuel
How Chromatin Stiffens Fibroblasts.
  • DOI:
    10.1016/j.cophys.2022.100537
  • 发表时间:
    2022-04
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
    Shuaishuai Hu;T. Vondriska
  • 通讯作者:
    Shuaishuai Hu;T. Vondriska
Taking Data Science to Heart: Next Scale of Gene Regulation.
  • DOI:
    10.1007/s11886-021-01467-6
  • 发表时间:
    2021-03-15
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Chapski DJ;Vondriska TM
  • 通讯作者:
    Vondriska TM
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Timothy McKinsey其他文献

Timothy McKinsey的其他文献

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{{ truncateString('Timothy McKinsey', 18)}}的其他基金

Advanced Small Animal Ultrasound Imaging - Vevo F2
先进的小动物超声成像 - Vevo F2
  • 批准号:
    10632878
  • 财政年份:
    2023
  • 资助金额:
    $ 72.05万
  • 项目类别:
Small molecule therapies targeting chromatin architecture in heart failure
针对心力衰竭染色质结构的小分子疗法
  • 批准号:
    10312765
  • 财政年份:
    2019
  • 资助金额:
    $ 72.05万
  • 项目类别:
Regulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.
BRD4 溴结构域蛋白对心力衰竭中染色质信号传导的调节。
  • 批准号:
    10219336
  • 财政年份:
    2015
  • 资助金额:
    $ 72.05万
  • 项目类别:
Regulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.
BRD4 溴结构域蛋白对心力衰竭中染色质信号传导的调节。
  • 批准号:
    10434776
  • 财政年份:
    2015
  • 资助金额:
    $ 72.05万
  • 项目类别:
Regulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.
BRD4 溴结构域蛋白对心力衰竭中染色质信号传导的调节。
  • 批准号:
    9975206
  • 财政年份:
    2015
  • 资助金额:
    $ 72.05万
  • 项目类别:
Regulation of Cardiac Signaling by Class I Histone Deacetylases
I 类组蛋白脱乙酰酶对心脏信号传导的调节
  • 批准号:
    10219331
  • 财政年份:
    2013
  • 资助金额:
    $ 72.05万
  • 项目类别:
Regulation of Cardiac Signaling by Class I Histone Deacetylases
I 类组蛋白脱乙酰酶对心脏信号传导的调节
  • 批准号:
    8577925
  • 财政年份:
    2013
  • 资助金额:
    $ 72.05万
  • 项目类别:
Regulation of Cardiac Signaling by Class I Histone Deacetylases
I 类组蛋白脱乙酰酶对心脏信号传导的调节
  • 批准号:
    8716810
  • 财政年份:
    2013
  • 资助金额:
    $ 72.05万
  • 项目类别:
Isoform-Selective HDAC Inhibitors for Age-Associated Diastolic Dysfunction
异构体选择性 HDAC 抑制剂治疗年龄相关舒张功能障碍
  • 批准号:
    8548228
  • 财政年份:
    2012
  • 资助金额:
    $ 72.05万
  • 项目类别:
Isoform-Selective HDAC Inhibitors for Age-Associated Diastolic Dysfunction
异构体选择性 HDAC 抑制剂治疗年龄相关舒张功能障碍
  • 批准号:
    8430402
  • 财政年份:
    2012
  • 资助金额:
    $ 72.05万
  • 项目类别:

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Development of palladium-catalyzed novel organic transformations of silylated allyl acetates
钯催化的硅烷化乙酸烯丙酯新型有机转化的开发
  • 批准号:
    18K05101
  • 财政年份:
    2018
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  • 项目类别:
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Biosynthesis of Methylketones and 2-Alkany l Acetates
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  • 批准号:
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