Imaging Histone Deacetylase in the Heart and Bone Marrow

心脏和骨髓中的组蛋白脱乙酰酶成像

• 批准号: 9753032
• 负责人: David E Sosnovik
• 金额: $ 82.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753032
• 关键词: 3-Dimensional; Affect; Affinity; Age; Age Distribution; Aging; Animal Model; Aortic Valve Stenosis; Architecture; Attenuated; Binding; Biological Markers; Blood; Body Weight; Body mass index; Bone Marrow; Brain; Cicatrix; DNA; Data; Development; Diabetes Mellitus; EFRAC; Elderly; Enzymes; Failure; Female; Fibrosis; Functional disorder; Gender; Gene Expression; Genetic Transcription; HDAC4 gene; Heart; Heart Diseases; Heart failure; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Hypertrophy; Image; Inflammatory; Injections; Kinetics; Left Ventricular Hypertrophy; Left Ventricular Mass; Lung; Magnetic Resonance; Measures; Mechanics; Medical; Metabolic; Molecular; Molecular Conformation; Morbidity - disease rate; Motion; Myocardial; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Obesity; Pathogenesis; Pathologic Processes; Pathway interactions; Patient imaging; Patients; Pharmaceutical Preparations; Physiology; Play; Positron-Emission Tomography; Pre-Clinical Model; Prevention; Process; Public Health; Reproducibility; Role; Scanning; Schedule; Specificity; System; Techniques; Tissues; Tracer; Treatment Failure; Vorinostat; adiponectin; aortic valve replacement; attenuation; biomarker development; circulating biomarkers; coronary fibrosis; cytokine; experimental study; healthy volunteer; heart function; heart imaging; in vivo; insight; male; monocyte; mortality; mouse model; non-invasive imaging; novel; novel therapeutic intervention; preclinical study; preservation; radiotracer; response; uptake

Project Summary Heart failure with preserved ejection fraction (HFpEF) is frequently accompanied by left ventricular hypertrophy (LVH) and myocardial fibrosis. The pathogenesis of these processes, however, remains poorly understood. In addition, no medical therapies have been developed that consistently attenuate the development of myocardial fibrosis and cause it to regress. Histone Deacetylases (HDACs) are a class of enzymes that cause conformational changes in the 3D architecture of DNA, modifying its transcription. Class I HDACs, in particular, have been implicated in the development of LVH and myocardial fibrosis. In preclinical models, HDAC inhibition attenuates these pathological processes and preserves the integrity of the myocardium. However, the role of HDACs in the human heart, and the utility of HDAC inhibition, remains unknown. We have recently developed a novel radiotracer, 11C-Martinostat, which binds with high affinity to class I HDACs. Preliminary studies have been performed in six healthy volunteers and show that the agent accumulates strongly in the myocardium and bone marrow, while being rapidly washed out of the blood pool and lungs. Blocking studies with suberanilohydroxamic acid (SAHA) in a large animal model confirm the specificity of 11C-Martinostat uptake in these tissues. We now aim to use 11C-Martinostat to further characterize the role of HDAC expression in the development of LVH and fibrosis. In addition to myocardial HDAC expression, we aim to assess whether HDAC expression in the bone marrow affects the secretion of fibrosis-modulating monocytes and cytokines. In aim 1 of the proposal, the impact of age, gender and diabetes on HDAC activity in the heart and bone marrow will be characterized. In aim 2, patients with severe aortic stenosis will be imaged to determine whether 11C-Martinostat uptake correlates with the degree of LVH and myocardial fibrosis. In aim 3, repeat imaging of these patients will be performed 6 months after transcatheter aortic valve replacement (TAVR) to correlate HDAC activity with changes in LVH and fibrosis. Imaging in all cases will be performed on a commercial whole body PET-MR system, allowing MR-derived metrics of myocardial function and fibrosis to be integrated with the PET readout of HDAC expression. Completion of the proposed studies will provide important insights into the role of HDACs in the human heart and bone marrow during aging, LVH and HFpEF. The uptake of 11C-Martinostat in the heart could provide a valuable biomarker to help guide the development of novel anti-fibrotic therapies, and is thus of major medical and

项目概要 射血分数保留的心力衰竭 (HFpEF) 常伴有左心室肥厚 （左心室肥厚）和心肌纤维化。然而，这些过程的发病机制仍然知之甚少。在 此外，目前还没有开发出能够持续减弱心肌病发展的药物疗法。 纤维化并使其消退。组蛋白脱乙酰酶 (HDAC) 是一类酶，可导致 DNA 3D 结构的构象变化，改变其转录。 I 类 HDAC，特别是， 与 LVH 和心肌纤维化的发生有关。在临床前模型中，HDAC 抑制减弱这些病理过程并保持心肌的完整性。然而， HDAC 在人类心脏中的作用以及 HDAC 抑制的效用仍然未知。我们最近有 开发了一种新型放射性示踪剂 11C-Martinostat，它与 I 类 HDAC 具有高亲和力结合。初步的 对六名健康志愿者进行的研究表明，该物质在体内大量积累 心肌和骨髓，同时被迅速从血池和肺部冲走。阻断研究 在大型动物模型中使用辛二苯异羟肟酸 (SAHA) 证实了 11C-Martinostat 的特异性 这些组织中的摄取。我们现在的目标是使用 11C-Martinostat 进一步表征 HDAC 的作用 LVH 和纤维化发展中的表达。除了心肌 HDAC 表达之外，我们的目标是 评估骨髓中的 HDAC 表达是否影响纤维化调节单核细胞的分泌 和细胞因子。在提案的目标 1 中，年龄、性别和糖尿病对心脏 HDAC 活性的影响 并对骨髓进行表征。在目标 2 中，严重主动脉瓣狭窄的患者将接受影像检查 确定 11C-Martinostat 摄取是否与 LVH 和心肌纤维化程度相关。在目标 3 中， 这些患者将在经导管主动脉瓣置换术后 6 个月进行重复成像 (TAVR) 将 HDAC 活性与 LVH 和纤维化的变化相关联。所有情况下的成像均将在 商用全身 PET-MR 系统，允许 MR 衍生的心肌功能和纤维化指标 与 HDAC 表达的 PET 读数集成。完成拟议的研究将提供 关于 HDAC 在衰老、LVH 和 HFpEF 过程中人类心脏和骨髓中的作用的重要见解。 心脏中 11C-Martinostat 的摄取可以提供有价值的生物标志物来帮助指导心脏的发育 新型抗纤维化疗法，因此具有重要的医学和