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: 10171890
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171890
• 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; antifibrotic treatment; 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

项目摘要 心力衰竭和保留的射血分数（HFPEF）经常伴有左心室肥大 （LVH）和心肌纤维化。然而，这些过程的发病机理仍然很少了解。在 此外，尚未开发出医疗疗法，从而始终如一地衰减心肌的发展 纤维化并导致其退化。组蛋白脱乙酰基酶（HDACS）是一类引起的酶 DNA的3D体系结构中的构象变化，修饰其转录。特别是I类HDACS 与LVH和心肌纤维化的发展有关。在临床前模型中，HDAC 抑制作用减轻了这些病理过程，并保留心肌的完整性。但是， HDAC在人心脏中的作用以及HDAC抑制的实用性仍然未知。我们最近有 开发了一种新型的放射性示踪剂11c-martinottat，该抗力与I类HDAC相结合。初步的 研究已经在六名健康志愿者中进行，表明该药物在 心肌和骨髓，同时被迅速从血池和肺部冲出。阻止研究 大型动物模型中的suberanilohydroxamic Acid（SAHA）证实了11C-MARTINOTTAT的特异性 在这些组织中的吸收。现在，我们的目标是使用11c-martinostat来进一步表征HDAC的作用 LVH和纤维化发育中的表达。除了心肌HDAC表达外，我们的目标是 评估骨髓中的HDAC表达是否影响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中HDAC活动的影响 和骨髓将被描述。在AIM 2中，将对患有严重主动脉狭窄的患者成像 确定11c-Martinottat摄取是否与LVH和心肌纤维化程度相关。在AIM 3中， 这些患者的重复成像将在经导管主动脉瓣更换后6个月进行 （TAVR）将HDAC活性与LVH和纤维化的变化相关联。在所有情况下都会进行成像 商业的全身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。拟议研究的完成将提供 对HDAC在衰老，LVH和HFPEF期间HDAC在人心脏和骨髓中的作用的重要见解。 心脏中11c-Martinostat的吸收可以提供有价值的生物标志物，以帮助指导发展 新型的抗纤维化疗法，因此是主要的医学和

项目成果

Magnetic Resonance-Based Characterization of Myocardial Architecture.

• DOI: 10.1016/j.hfc.2020.08.007
• 发表时间: 2021-01
• 期刊: Heart failure clinics
• 影响因子: 3.4
• 作者: Sosnovik DE