Imaging Histone Deacetylase in the Heart and Bone Marrow

项目摘要 射血分数保留性心力衰竭（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 此外，还没有开发出一致地减弱心肌梗塞发展的药物疗法。 纤维化并使其退化。组蛋白脱乙酰基酶（HDAC）是一类酶， DNA的3D结构中的构象变化，修改其转录。特别是I类HDAC， 与LVH和心肌纤维化的发生有关。在临床前模型中， 抑制减弱这些病理过程并保持心肌的完整性。但 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 开发了一种新的放射性示踪剂，11 C-Martinostat，其以高亲和力结合I类HDAC。初步 在六名健康志愿者中进行的研究表明，该试剂在 心肌和骨髓，同时被迅速从血池和肺中冲洗出来。阻断研究 在大型动物模型中使用辛二酰异羟肟酸（SAHA）证实了11 C-Martinostat的特异性 在这些组织中。我们现在的目标是使用11 C-Martinostat进一步表征HDAC的作用 在LVH和纤维化的发展中表达。除了心肌HDAC表达外，我们的目标是 评估骨髓中HDAC表达是否影响纤维化调节单核细胞的分泌 和细胞因子。在该提案的目标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，将对患有严重主动脉瓣狭窄的患者进行成像， 确定11 C-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）以将HDAC活性与LVH和纤维化的变化相关联。所有病例的成像均将在 商业全身PET-MR系统，允许心肌功能和纤维化的MR衍生指标， 与HDAC表达的PET读数整合。完成拟议的研究将提供 对HDAC在衰老、LVH和HFpEF期间在人类心脏和骨髓中的作用的重要见解。 心脏中11 C-Martinostat的摄取可以提供一种有价值的生物标志物，以帮助指导心脏疾病的发展。 新型抗纤维化疗法，因此是主要的医疗和

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