Targeting HDAC6 to Modulate Titin Stiffness for Dilated Cardiomyopathy Therapy

项目摘要/摘要 扩张型心肌病(DCM)与心脏收缩/泵功能受损有关，这可能导致 导致心力衰竭和死亡。据估计，美国每250名成年人中就有1人患有DCM，其中约40%的人患有DCM 被归因于遗传原因。DCM的一个共同特征是Titin的刚性降低。Titin是一种 分子弹簧通过在收缩单位内发挥作用，为心脏提供被动张力，称为 肌原纤维。认为在扩张型心肌病患者中重建肌动蛋白弹性功能(即肌动蛋白硬化)可以提供 一种治疗心肌病的创新的、改善疾病的方法。我们的合作者未发表的发现， 麦肯锡博士揭示了细胞质蛋白组蛋白脱乙酰酶6(HDAC6)控制 Titin的僵硬。拟议工作的长期目标是开发一种选择HDAC6的小分子 分子抑制剂作为肌动蛋白的强化剂，用于改善人体的收缩功能和治疗扩张型心肌病。这是一致的 NHLBI的使命，包括治疗心脏病以增强个人健康，因此他们 可以活得更长、更充实。一个具体的目标是对新的HDAC6抑制剂进行排序(由发现 Eikonizo Treeutics)提高培养的成年大鼠心肌细胞肌动蛋白硬度的能力，以及他们的 在短期心力衰竭小鼠模型中改善收缩功能的能力。在第二个特定目标中， 通过这些初始过滤的化合物将在DCM大鼠模型中进行有效性测试 通过严重的肌动蛋白软化。这个大鼠模型概括了RBM20(RNA结合基序蛋白20， 一种针对Titin)心肌病的剪接因子，这是一种人类侵袭性和早发性遗传性DCM。这 药物发现提案有可能促进治疗扩张型心肌炎的变革性疗法的开发 在人类身上。

PROJECT SUMMARY/ABSTRACT Dilated cardiomyopathy (DCM) is associated with impaired systolic/pump function of the heart, which can lead to heart failure and death. It is estimated that 1 in 250 adults in the U.S. have DCM, with ~40% of these cases being attributed to genetic causes. A common characteristic of DCM is reduced stiffness of titin. Titin is a molecular spring that provides passive tension to the heart by functioning within contractile units known as myofibrils. It is believed that re-establishing titin spring function (i.e. stiffening titin) in DCM patients could provide an innovative, disease-modifying approach to treat cardiomyopathy. Unpublished findings from our collaborator, Dr. McKinsey, reveal a remarkable ability of the cytoplasmic protein, histone deacetylase 6 (HDAC6), to control the stiffness of titin. The long-term objective of the proposed work is to develop an HDAC6-selective small molecule inhibitor as a ‘titin stiffener’ to improve systolic function and treat DCM in humans. This is in-line with the mission of the NHLBI, which includes treatment of heart disease to enhance the health of individuals so they can live longer and more fulfilling lives. One specific aim is to rank-order novel HDAC6 inhibitors (discovered by Eikonizo Therapeutics) for their ability to increase titin stiffness in cultured adult rat cardiomyocytes, and for their ability to improve systolic cardiac function in a short-term mouse model of heart failure. In a second specific aim, compounds that advance through these initial filters will be tested for efficacy in a rat model of DCM characterized by severe titin softening. This rat model recapitulates many elements of RBM20 (RNA-binding motif protein 20, a splicing factor that targets titin) cardiomyopathy, an aggressive and early onset genetic DCM in humans. This drug discovery proposal has the potential to facilitate the development of transformative therapies to treat DCM in humans.