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

项目总结