舒张性心衰(HFpEF)的动物模型：机理研究和实验治疗

Recent studies demonstrate that almost half of heart failure patients have impaired relaxation, known as diastolic dysfunction and diastolic heart failure with preserved ejection fraction (HFpEF). HFpEF can be caused by various disorders and pathological changes, such as hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM) and primary hypertension, etc. However, the mechanism is still unknown. The long-term goal of our laboratory is to explore the mechanisms of diastolic dysfunction, HFpEF and develop targeting pharmaceuticals that can be used to treat the disorders. Our laboratory is among the first in studying the molecular mechanisms and pathophysiology of diastolic dysfunction in transgenic mouse models. In our previous studies, we have discovered that the hypersensitivity of myofibrils for Ca2+ is a key factor that is associated with impaired relaxation in myocardial cells. Now the animal models created by the applicant have been successfully transported to Chongqing Medical University. In this proposal, we will use these animal models to test the central hypothesis that desensitization of myofibrils to Ca2+ by catechins can precisely target the disease molecules, reverse impaired relaxation and treat the disease. As such, the proposed specific aims will determine the cellular mechanisms underlying diastolic dysfunction and test the effects of desensitizing catechins on correcting Ca2+ hypersensitivity and reversing diastolic dysfunction in mouse models as well as human patients with RCM. Furthermore, we will create novel mouse lines modeling new troponin mutations recently discovered in RCM patients from Chongqing Medical University Children’s Hospital to further confirm the role of troponin and its mutations on HFpEF.

最近研究发现约一半的心衰患者患有舒张功能障碍而其收缩功能基本正常，即舒张性心衰。诸多疾病，如肥厚型和限制型心肌病，均可以导致舒张功能障碍以及晚期的心衰, 但其机理尚不明确。本研究室一直在该领域的前端利用我们自己建立的动物舒张功能障碍模型进行探讨。在本课题中，我们的科研假设是：在钙调蛋白突变造成的心肌舒张功能障碍中，心肌纤维对钙离子的高敏感是导致心肌细胞舒张受损的一个重要原因，降低钙敏可以精准地针对疾病靶分子以改善心脏舒张功能并治疗患舒张功能障碍的疾病动物和病人。本课题申请人已将独立创建的转基因小鼠动物模型成功地转运至该课题依托单位-重庆医科大学实验动物中心繁殖。在本课题中，我们将建立四个实验目标，并应用此动物模型从分子、细胞和整体动物水平来揭示舒张功能障碍的机理。另外利用我们最近新发现的中国西南地区引起舒张功能障碍的钙调蛋白新突变，建立新的动物模型进一步证实突变基因与心脏舒张功能的关系。

最近研究发现约一半的心衰患者患有舒张功能障碍而其收缩功能基本正常，即舒张性心衰。诸多疾病，如肥厚型和限制型心肌病，均可以导致舒张功能障碍以及晚期的心衰，但其机理尚不明确。本研究室一直在该领域的前端利用我们自己建立的动物舒张功能障碍模型进行探讨。在本课题中，我们的科研假设是：在钙调蛋白突变造成的心肌舒张功能障碍中，心肌纤维对钙离子的高敏感是导致心肌细胞舒张受损的一个重要原因，降低钙敏可以精准地针对疾病靶分子以改善心脏舒张功能并治疗患舒张功能障碍的疾病动物和病人。本课题申请人已将独立创建的转基因小鼠动物模型成功地转运至该课题依托单位-重庆医科大学实验动物中心繁殖。在本课题中，我们将建立四个实验目标，并应用此动物模型从分子、细胞和整体动物水平来揭示舒张功能障碍的机理。另外利用我们最近新发现的中国西南地区引起舒张功能障碍的钙调蛋白新突变，建立新的动物模型进一步证实突变基因与心脏舒张功能的关系。