Targeting HDAC6 to Modulate Titin Stiffness for Dilated Cardiomyopathy Therapy

项目总结/摘要 扩张型心肌病（DCM）与心脏的收缩/泵功能受损相关，这可导致 心脏衰竭和死亡据估计，美国每250名成年人中就有1人患有DCM，其中约40%的病例 被认为是遗传原因。DCM的一个共同特征是肌联蛋白的刚度降低。Titin是一个 一种分子弹簧，通过在收缩单位内起作用， 肌原纤维据信，在DCM患者中重建肌联蛋白弹簧功能（即，硬化肌联蛋白）可以提供 一种治疗心肌病的创新的、改变疾病的方法。我们的合作者未发表的发现， 博士McKinsey的研究揭示了细胞质蛋白组蛋白去乙酰化酶6（HDAC 6）控制细胞凋亡的显著能力。 肌联蛋白的硬度拟议工作的长期目标是开发HDAC 6选择性小 分子抑制剂作为“肌联蛋白加强剂”，以改善收缩功能和治疗人类DCM。这是符合 NHLBI的使命，其中包括治疗心脏病，以提高个人的健康， 可以活得更久更充实一个具体的目的是对新的HDAC 6抑制剂（由N.A. Eikonizo Therapeutics）在培养的成年大鼠心肌细胞中增加肌联蛋白刚度的能力，以及它们在培养的成年大鼠心肌细胞中增加肌联蛋白刚度的能力。 改善心力衰竭短期小鼠模型中心脏收缩功能的能力。在第二个具体目标中， 将在DCM大鼠模型中测试通过这些初始过滤器的化合物的功效， 肌联蛋白严重软化该大鼠模型重现了RBM 20的许多元件（RNA结合基序蛋白20， 一种靶向肌联蛋白心肌病的剪接因子，肌联蛋白心肌病是一种侵袭性和人类早期发病的遗传性扩张型心肌病。这 药物发现提案有可能促进治疗DCM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 Unpublished findings from our collaborator, Dr.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.