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

基本信息

批准号：
8430402
负责人：
Timothy McKinsey
金额：
$ 23.11万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8430402
关键词：
Address Adult Age Aging American Anti-Inflammatory Agents Anti-inflammatory Cardiac Caring Cells Chronic Clinic Clinical Clinical Trials Data Development Diagnosis Diastolic heart failure EFRAC Economic Burden Enzymes Epidemiologic Studies Excision Female Fibrosis Foundations Functional disorder Genes Goals Health Healthcare Systems Heart Heart Block Heart Hypertrophy Heart failure Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Histones Human Hypertension Infiltration Inflammation Inflammatory Innovative Therapy Investigation Living Standards Longevity Lysine Malignant Neoplasms Marketing Mediating Modeling Molecular Pathogenesis Patients Pharmaceutical Preparations Prevalence Protein Isoforms Proteins Public Health Recording of previous events Regulatory T-Lymphocyte Reporting Research Risk Factors Rodent Model Role Symptoms Systolic heart failure United States Ventricular age related base cost design drug discovery effective therapy falls heart function improved innovation insight interstitial novel novel therapeutics

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to address the role of a subset of histone deacetylase (HDAC) enzymes, class I HDACs, in the control of diastolic heart failure. Each year more than 600,000 cases of heart failure (HF) are diagnosed in the United States, adding to the more than 5 million adults with this condition; costs of care are estimated at $34.8 billion per year. About half of these patients have heart failure with preserved ejection fraction (HFpEF), or diastolic heart failure. Aging and hypertension are major risk factors for the development of HFpEF. Over the last two decades, systolic heart failure (sHF) patients have seen clinical benefits through pharmacological management; unfortunately, standard-of-care sHF medications have failed to show efficacy in large clinical trials in patients with HFpEF. Histone deacetylases (HDACs) catalyze removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and fall into four classes (I, II, III and IV). Broad-spectrum, 'pan' inhibitors of HDAC catalytic activity are marketd for cancer. Our preliminary data demonstrate that pan-HDAC inhibition is profoundly protective in a rodent model of HFpEF induced by chronic hypertension. HDAC inhibition blocked cardiac hypertrophy and fibrosis, improved diastolic cardiac function, and prolonged lifespan even in the face of sustained hypertension. In subsequent studies we determined that class I HDAC- selective inhibition blocks cardiac fibrosis through a mechanism associated with induction of anti-inflammatory regulatory T cells (Tregs). These results suggest an unanticipated application for isoform-selective HDAC inhibitors for the treatment of human HFpEF. This proposal is designed to address the overall hypothesis that class I HDACs promote diastolic dysfunction in the aging heart by triggering ventricular inflammation and fibrosis. Results from these studies should provide novel insights into the molecular basis of diastolic heart failure, and could form the foundation for innovative approaches to drug discovery for HFpEF based on isoform- selective HDAC inhibition. PUBLIC HEALTH RELEVANCE: Heart failure is a major health problem and growing economic burden worldwide. With greater than five million heart failure patients in the U.S. alone, treatment of this condition represents an estimated annual cost to the American health care system of over $37 billion. The research outlined in this proposal should provide a foundation for discovery of novel therapeutics to treat patient suffering from age-related cardiac dysfunction.

描述（由申请人提供）：该项目的目的是解决组蛋白脱乙酰基酶（HDAC）酶（I类HDACS）的作用，在控制舒张性心力衰竭的控制中。每年在美国诊断出600,000例心力衰竭病例（HF），增加了500万成年人患有这种情况；护理费用估计为每年348亿美元。这些患者中约有一半的射血分数（HFPEF）或舒张期心力衰竭患有心力衰竭。衰老和高血压是主要危险因素 HFPEF的开发。在过去的二十年中，收缩性心力衰竭（SHF）患者通过药理学管理看到了临床益处。不幸的是，在HFPEF患者的大型临床试验中，护理标准SHF药物未能显示出功效。组蛋白脱乙酰基酶（HDACS）催化了各种蛋白质中赖氨酸残基的去除。 18个哺乳动物的HDAC由不同的基因编码，并分为四个类（I，II，III和IV）。 HDAC催化活性的广谱“ PAN”抑制剂是癌症的市场。我们的初步数据表明，在由慢性高血压引起的HFPEF模型中，PAN-HDAC抑制具有深远的保护。 HDAC抑制可阻止心脏肥大和纤维化，舒张性心脏功能的改善以及延长寿命，即使面对持续的高血压。在随后的研究中，我们确定I类HDAC-选择性抑制通过与抗炎调节T细胞（TREG）相关的机制来阻断心脏纤维化。这些结果表明，对于治疗人HFPEF的同工型选择性HDAC抑制剂的意外应用。该建议旨在解决总体假设，即I类HDAC通过触发心室炎症和纤维化促进衰老心脏的舒张功能障碍。这些研究的结果应为舒张性心力衰竭的分子基础提供新的见解，并可能为基于同工型HDAC抑制的HFPEF的创新方法构成基础。公共卫生相关性：心力衰竭是一个主要的健康问题，并且在全球范围内增加了经济负担。仅在美国就有超过500万心力衰竭的患者，对这种病情的治疗代表了美国医疗保健系统的每年成本超过370亿美元。该提案中概述的研究应为发现新型治疗剂的基础，以治疗患有与年龄相关的心脏功能障碍的患者。