Imaging Histone Deacetylase in the Heart and Bone Marrow

项目摘要 射血分数保留的心力衰竭(HFpEF)常伴有左心室肥厚 (LVH)和心肌纤维化。然而，这些过程的发病机制仍然知之甚少。在……里面 此外，目前还没有开发出能持续抑制心肌梗死发展的药物。 纤维化并使其消退。组蛋白脱乙酰酶(HDAC)是一类能引起 DNA三维结构的构象变化，改变了它的转录。尤其是I类HDAC， 已被认为与左心室肥厚和心肌纤维化的发生有关。在临床前模型中，HDAC 抑制作用减弱了这些病理过程，并保护了心肌的完整性。然而， HDAC在人类心脏中的作用以及HDAC抑制的作用尚不清楚。我们最近做了 开发了一种新型的放射性示踪剂11C-Martinostat，它与I类HDAC具有高亲和力。初步 在六名健康志愿者身上进行的研究表明，这种药物在体内积聚很强 心肌和骨髓，同时被迅速洗出血池和肺。阻断研究 在大型动物模型中用亚苯胺异羟肟酸(SAHA)证实11C-马替诺斯特的特异性 在这些组织中的摄取。我们现在的目标是使用11C-Martinostat来进一步表征HDAC的作用 在左心室肥厚和纤维化发生发展过程中的表达。除了心肌HDAC的表达，我们的目标是 评估骨髓中HDAC的表达是否影响调节纤维化的单核细胞的分泌 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活动的影响 而骨髓将被鉴定为。在目标2中，严重主动脉狭窄的患者将被成像到 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。所有情况下的成像都将在 一种商业全身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。建议的研究完成后，将提供 关于HDAC在人的心脏和骨髓在衰老、LVH和HFpEF过程中的作用的重要见解。 心脏对11C-Martinostat的摄取可以提供一个有价值的生物标志物来帮助指导高血压的发生。 新的抗纤维化疗法，因此具有重大的医学和

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