Deacetylase-Dependent Control of Diastolic Dysfunction and HFpEF
舒张功能障碍和 HFpEF 的脱乙酰酶依赖性控制
基本信息
- 批准号:9903434
- 负责人:
- 金额:$ 77.3万
- 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:2019-04-04 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAddressAdultAffectAgingAnimal ModelAnimalsCalciumCardiacCardiac MyocytesCardiopulmonaryCharacteristicsClinicalClinical TrialsCountryDeacetylaseDeacetylationDevelopmentDiagnosisDoseEFRACElementsEnzymesEpigenetic ProcessEvaluationFDA approvedFamilyFamily FelidaeFibroblastsFibrosisFoundationsFunctional disorderFutureGene Expression RegulationGenetic TranscriptionHDAC2 geneHealthHealth ExpendituresHeartHeart DiseasesHeart ResearchHeart failureHistone DeacetylaseHistone Deacetylase InhibitorHistonesHospitalizationHumanHypertensionImpairmentIndividualKnowledgeLaboratoriesLinkLongevityMapsMechanicsMedicalMedical ResearchMissionModelingMolecularMuscle CellsMyofibrilsNational Heart, Lung, and Blood InstituteOutcomePaperPathogenesisPatientsPharmaceutical PreparationsPharmacologyPharmacology StudyPhasePhenotypeProtein AcetylationProtein IsoformsProteinsProteomicsPublic HealthPublishingQuality of lifeRattusRelaxationResearchRodentRodent ModelRoleSarcoplasmic ReticulumSiteSpeedStructureSymptomsSyndromeTailTestingTherapeuticTherapeutic IndexTranslationsTreatment EfficacyTroponin IUnited StatesUnited States National Institutes of HealthVentricularWorkZolinzabasecare costsclinical translationcoronary fibrosisdesigndisabilityhead-to-head comparisonheart functionhistone acetyltransferasehospitalization ratesimprovedin vivoinhibitor/antagonistmortalitymouse modelnovelpatient responsepreservationpreventprimary outcomesexside effectsmall moleculeuptake
项目摘要
Project Summary/Abstract
Large clinical outcome trials with inhibitors of excess neurohormonal activity in heart failure (HF) with reduced
ejection fraction (HFrEF) patients have shown significant decreases in mortality. However, the effects of these
same neurohormonal inhibitors in HF with preserved ejection fraction (HFpEF) patients have consistently failed
to reach positive primary outcomes. The dichotomy in the responses of the patients likely results from
differences in HFpEF versus HFrEF pathophysiology, and the absence of experimental HFpEF models that
capture essential characteristics of this syndrome. Our contention, and the approach used in the proposed
work, is that concomitant use of a large animal HFpEF model and a mouse model of diastolic dysfunction with
preserved EF will enable us to document common effects of a putative therapeutic on the HFpEF phenotype,
thus facilitating translation of our findings to the estimated 2.5 million humans currently suffering from HFpEF in
the United States alone.
Within the last year, work by the two PIs of this proposal was the first to illustrate a crucial role for a family of
epigenetic regulatory enzymes, histone deacetylases (HDACs), in the control of diastolic dysfunction and
HFpEF pathogenesis. The McKinsey laboratory showed that a small molecule HDAC inhibitor prevented
diastolic dysfunction in rat and mouse models of diastolic dysfunction with preserved EF triggered by
hypertension or aging. Strikingly, the work was the first to link impairment of myofibril relaxation to the
development of diastolic dysfunction in rodents, as well as in humans with HFpEF. Furthermore, it was shown
that HDAC inhibition improves relaxation of the heart by promoting myofibrillar protein acetylation, thereby
speeding myofibril relaxation rates. The Houser laboratory has recently demonstrated similar beneficial effects
of an HDAC inhibitor in a feline model that recapitulates many elements of HFpEF in humans. The studies
proposed in this application would define a strategy for HDAC inhibition that provides the greatest therapeutic
efficacy, setting the stage for a proof-of-concept Phase 2a clinical trial with an HDAC inhibitor in patients with
HFpEF. Furthermore, the work would define which HDAC isoforms promote diastolic dysfunction, and expand
our understanding of the cellular and molecular mechanisms by which HDAC inhibitors improve relaxation of
the heart. Three independent specific aims are designed to significantly extend this new field of translational
cardiac research, and test the overall hypothesis that increased HDAC activity contributes to the
pathogenesis of HFpEF by promoting diastolic dysfunction via deacetylation of proteins that regulate myofibril
relaxation, cardiac fibrosis and/or sarcoplasmic reticulum calcium uptake.
项目总结/摘要
在心力衰竭(HF)患者中使用过量神经激素活性抑制剂的大型临床结局试验,
射血分数(HFrEF)患者的死亡率已显示出显著降低。然而,这些影响
在射血分数保留的HF(HFpEF)患者中,
达到积极的初步结果。患者反应的二分法可能是由于
HFpEF与HFrEF病理生理学的差异,以及缺乏实验HFpEF模型,
捕捉这种综合征的基本特征。我们的论点,以及建议中使用的方法
同时使用大动物HFpEF模型和舒张功能障碍小鼠模型,
保留的EF将使我们能够证明推定的治疗剂对HFpEF表型的共同作用,
从而促进了我们的研究结果在估计的250万目前患有HFpEF的人中的翻译,
美国单独。
在过去的一年里,这两个项目的工作是第一次说明一个家庭的关键作用,
表观遗传调节酶,组蛋白脱乙酰酶(HDAC),在舒张功能障碍的控制和
HFpEF发病机制。麦肯锡实验室表明,一种小分子HDAC抑制剂可以防止
舒张功能不全的大鼠和小鼠模型中的舒张功能不全,具有由
高血压或衰老。引人注目的是,这项工作是第一个将肌原纤维松弛损伤与
在啮齿类动物以及HFpEF患者中发生舒张功能障碍。此外,还显示,
HDAC抑制通过促进肌原纤维蛋白乙酰化改善心脏舒张,
加快肌原纤维松弛速率。豪泽实验室最近也证明了类似的有益效果
HDAC抑制剂在猫模型中的作用,该模型重现了人类HFpEF的许多元素。研究
本申请中提出的将定义一种HDAC抑制策略,
疗效,为HDAC抑制剂在患有以下疾病的患者中进行的概念验证2a期临床试验奠定基础
HFpEF。此外,这项工作将确定哪些HDAC亚型促进舒张功能障碍,并扩大
我们对HDAC抑制剂改善血管舒张的细胞和分子机制的理解,
心脏三个独立的具体目标旨在显着扩展这一新的翻译领域
心脏研究,并测试整体假设,增加HDAC活动有助于
通过调节肌原纤维的蛋白质脱乙酰化促进舒张功能障碍的HFpEF发病机制
松弛、心脏纤维化和/或肌浆网钙摄取。
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)
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Steven R Houser其他文献
Human Embryonic-Stem-Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts Embryonic Stem Cell–Derived Cardiac Myocytes Are Not Ready for Human Trials on Cutting Edge
人类胚胎干细胞来源的心肌细胞可再生非人类灵长类动物心脏胚胎干细胞来源的心肌细胞尚未准备好进行人体试验
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Mark E. Anderson;Joshua Goldhaber;Steven R Houser;Michel Pucéat;Mark A. Sussman - 通讯作者:
Mark A. Sussman
Steven R Houser的其他文献
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{{ truncateString('Steven R Houser', 18)}}的其他基金
Deacetylase-Dependent Control of Diastolic Dysfunction and HFpEF
舒张功能障碍和 HFpEF 的脱乙酰酶依赖性控制
- 批准号:
10371078 - 财政年份:2019
- 资助金额:
$ 77.3万 - 项目类别:
Deacetylase-Dependent Control of Diastolic Dysfunction and HFpEF
舒张功能障碍和 HFpEF 的脱乙酰酶依赖性控制
- 批准号:
9762284 - 财政年份:2019
- 资助金额:
$ 77.3万 - 项目类别:
Compartmental PKA and Pathological Cardiac Hypertrophy
室室 PKA 和病理性心脏肥大
- 批准号:
10018665 - 财政年份:2018
- 资助金额:
$ 77.3万 - 项目类别:
Cortical Bone Stem Cell Therapy for the Infarcted Heart
皮质骨干细胞治疗梗塞心脏
- 批准号:
9926124 - 财政年份:2018
- 资助金额:
$ 77.3万 - 项目类别:
Compartmental PKA and Pathological Cardiac Hypertrophy
室室 PKA 和病理性心脏肥大
- 批准号:
10201728 - 财政年份:2018
- 资助金额:
$ 77.3万 - 项目类别:
Paracrine hypothesis underlying cardiac stem cell therapy
心脏干细胞治疗的旁分泌假说
- 批准号:
9193398 - 财政年份:2016
- 资助金额:
$ 77.3万 - 项目类别:
Paracrine hypothesis underlying cardiac stem cell therapy
心脏干细胞治疗的旁分泌假说
- 批准号:
9313922 - 财政年份:2016
- 资助金额:
$ 77.3万 - 项目类别:
TRPC Channel Regulation of Cardiac Hypertrophy and Contractility
TRPC 通道对心脏肥大和收缩力的调节
- 批准号:
8760769 - 财政年份:2014
- 资助金额:
$ 77.3万 - 项目类别:
TRPC Channel Regulation of Cardiac Hypertrophy and Contractility
TRPC 通道对心脏肥大和收缩力的调节
- 批准号:
9039136 - 财政年份:2014
- 资助金额:
$ 77.3万 - 项目类别:
TRPC Channel Regulation of Cardiac Hypertrophy and Contractility
TRPC 通道对心脏肥大和收缩力的调节
- 批准号:
8916819 - 财政年份:2014
- 资助金额:
$ 77.3万 - 项目类别:
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