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：
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
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：
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

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.

项目摘要/摘要大型临床结局试验患有心力衰竭过多的神经激素活性（HF）的抑制剂降低射血分数（HFREF）患者的死亡率显着降低。但是，这些影响 HF中具有射血分数（HFPEF）患者的HF中相同的神经激素抑制剂一直失败达到积极的主要结果。患者反应中的二分法可能是由 HFPEF与HFREF病理生理学的差异，以及缺乏实验性HFPEF模型捕获该综合征的基本特征。我们的争论以及拟议的方法工作，是伴随使用大型动物HFPEF模型和舒张功能障碍的小鼠模型保留的EF将使我们能够记录假定治疗对HFPEF表型的常见影响，因此，促进了我们的发现转化给目前估计有250万人类的HFPEF 仅美国。在过去的一年中，该提案的两个PI的工作是第一个说明一个家庭的关键作用表观遗传调节酶，组蛋白脱乙酰基酶（HDACS），控制舒张功能障碍和 HFPEF发病机理。麦肯锡实验室表明，一个小分子HDAC抑制剂阻止了舒张功能障碍的舒张功能障碍和舒张功能障碍的小鼠模型，并触发的EF触发。高血压或衰老。令人惊讶的是，这项工作是第一个将肌原纤维放松障碍障碍联系起来的工作啮齿动物以及患有HFPEF的人的舒张功能障碍的发展。此外，它显示了 HDAC抑制通过促进肌原纤维蛋白乙酰化改善心脏的放松，从而改善心脏的放松加速肌纤维松弛率。 Houser实验室最近显示出类似的有益作用 HDAC抑制剂在猫科动物模型中概括了人类HFPEF的许多元素。研究在本应用程序中提出的将定义HDAC抑制策略，以提供最大的治疗性功效，为患有HDAC抑制剂的概念证明临床试验奠定了基础 HFPEF。此外，这项工作将定义哪些HDAC同工型促进舒张功能障碍，并扩展我们对HDAC抑制剂改善松弛的细胞和分子机制的理解心。三个独立的特定目标旨在显着扩展这一新的翻译领域心脏研究并检验了HDAC活性增加的总体假设有助于通过调节肌原纤维的蛋白质的脱乙酰化促进舒张功能障碍，通过促进舒张功能障碍来促进HFPEF的发病机理松弛，心脏纤维化和/或肌浆网钙吸收。