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
• 负责人: Steven R Houser
• 金额: $ 79.89万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9762284
• 关键词: Acetylation; Address; Adult; Affect; Aging; Animal Model; Animals; Calcium; Cardiac; Cardiac Myocytes; Cardiopulmonary; Characteristics; Clinical; Clinical Trials; Country; Deacetylase; Deacetylation; Development; Diagnosis; Dose; EFRAC; Elements; Enzymes; Epigenetic Process; Evaluation; FDA approved; Family; Family Felidae; Fibroblasts; Fibrosis; Foundations; Functional disorder; Future; Gene Expression Regulation; Genetic Transcription; HDAC2 gene; Health; Health Expenditures; Heart; Heart Diseases; Heart Research; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Hospitalization; Human; Hypertension; Impairment; Individual; Knowledge; Laboratories; Link; Longevity; Maps; Mechanics; Medical; Medical Research; Mission; Modeling; Molecular; Muscle Cells; Myofibrils; National Heart, Lung, and Blood Institute; Outcome; Paper; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phenotype; Protein Acetylation; Protein Isoforms; Proteins; Proteomics; Public Health; Publishing; Quality of life; Rattus; Relaxation; Research; Rodent; Rodent Model; Role; Sarcoplasmic Reticulum; Site; Speed; Structure; Symptoms; Syndrome; Tail; Testing; Therapeutic; Therapeutic Index; Translations; Treatment Efficacy; Troponin I; United States; United States National Institutes of Health; Ventricular; Work; Zolinza; base; care costs; clinical translation; coronary fibrosis; design; disability; head-to-head comparison; heart function; histone acetyltransferase; hospitalization rates; improved; in vivo; inhibitor/antagonist; mortality; mouse model; novel; patient response; preservation; prevent; primary outcome; sex; side effect; small molecule; uptake

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.

项目摘要/摘要 使用过度神经激素活性抑制剂治疗心力衰竭(HF)的大型临床结果试验 射血分数(HFrEF)患者的死亡率显著降低。然而，这些影响 射血分数保留(HFpEF)的心力衰竭患者使用相同的神经激素抑制剂一直失败 以达到积极的初步结果。患者反应的二分法可能是由于 HFpEF和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，以及在建议的 工作是同时使用大型动物HFpEF模型和小鼠舒张期功能障碍模型 保存EF将使我们能够记录假定的治疗对HFpEF表型的共同影响， 从而便于将我们的发现翻译到估计为250万目前患有HFpEF的人身上 仅美国一国。 在过去的一年里，这项提案的两个PI的工作第一次说明了一个家庭的关键作用 表观遗传调节酶，组蛋白脱乙酰酶(HDACs)，在控制舒张期功能障碍和 HFpEF的发病机制。麦肯锡实验室表明，一种小分子HDAC抑制剂可以预防 大鼠和小鼠的舒张期功能不全模型 高血压或衰老。引人注目的是，这项研究首次将肌原纤维松弛障碍与 在啮齿类动物和患有HFpEF的人类中，舒张期功能障碍的发展。此外，它还显示了 抑制HDAC通过促进肌原纤维蛋白乙酰化来改善心脏的松弛，从而 肌原纤维松弛速度加快。豪泽实验室最近也证明了类似的有益效果。 在猫模型中发现了一种HDAC抑制剂，该模型概括了人类体内HFpEF的许多元素。这些研究 在本申请中提出的将定义一种抑制HDAC的策略，该策略提供最大的治疗效果 有效性，为使用HDAC抑制剂进行2a期概念验证临床试验奠定了基础 HFpEF。此外，这项工作将定义哪些HDAC亚型促进舒张期功能障碍，并扩大 我们对HDAC抑制剂改善血管松弛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著扩展这一新的翻译领域 心脏研究，并检验增加HDAC活动有助于 HFpEF通过肌原纤维调节蛋白去乙酰化促进舒张期功能障碍的发病机制 松弛、心肌纤维化和/或肌浆网钙摄取。