sFlt and Metabolic Mechanisms of Peripartium Cardiomyopathy

 描述（由申请人提供）：围产期心肌病（PPCM）的特征是妊娠晚期或分娩后不久的女性心脏收缩功能丧失。PPCM影响全球约1：1000的出生，并经常导致慢性心力衰竭，需要心脏移植或死亡。因此，这种疾病对本来健康的年轻妇女及其新家庭可能是毁灭性的。PPCM的机制知之甚少。我们最近提出了一个新的概念，即PPCM是一种血管疾病，由妊娠后期胎盘分泌的强效抗血管因子引发。这些因子中最值得注意的是sFlt 1，一种可溶性诱饵受体和VEGF抑制剂。我们建议在这里正式测试这一假设，通过抑制sFlt 1分泌在怀孕期间的PPCM小鼠模型。我们还建议深入研究sFlt 1引起心肌病的机制。我们假设sFlt 1通过VEGFR 2和VEGFR 1中和VEGF信号，从而分别对心脏血管密度和营养通量产生不利影响。该假设将通过转基因小鼠模型、细胞培养实验以及最先进的心脏代谢分析和成像方式进行验证。最后，我们最近的人类遗传学数据表明，许多患有PPCM的女性在肌联蛋白（一种大型肌节蛋白）中存在突变。我们假设这些突变在怀孕期间和暴露于过量的sFlt 1时易导致血管/代谢崩溃，并将用转基因小鼠和sFlt 1的病毒递送来测试这一概念。这些研究的成功将为PPCM（一种知之甚少的疾病）提供机制上的见解，并将为目前尚无特异性治疗的疾病开辟新的治疗方法。

 DESCRIPTION (provided by applicant): Peripartum cardiomyopathy (PPCM) is marked by loss of cardiac contractile function in women late in pregnancy or soon after delivery. PPCM affects approximately 1:1000 births worldwide, and frequently leads to chronic heart failure, need for cardiac transplant, or death. The disease can thus be devastating to otherwise healthy young women and their new families. Little is known of the mechanisms underlying PPCM. We have recently proposed the novel notion that PPCM is a vascular disease, triggered by the secretion of potent anti- vascular factors from the placenta late during gestation. Most notable among these factors is sFlt1, a soluble decoy receptor and VEGF inhibitor. We propose here to formally test this hypothesis by inhibiting sFlt1 secretion during pregnancy in a murine model of PPCM. We also propose to delve into the mechanisms by which sFlt1 causes cardiomyopathy. We hypothesize that sFlt1 neutralizes VEGF signaling via both VEGFR2 and VEGFR1, thereby adversely affecting cardiac vascular density and nutrient flux, respectively. The hypothesis will be tested with genetically modified mouse models, cell culture experiments, and state-of- the-art assays and imaging modalities of cardiac metabolism. Finally, our recent human genetic data indicate that many women with PPCM bear mutations in titin, a large sarcomeric protein. We hypothesize that these mutations predispose to vascular/metabolic collapse during pregnancy and exposure to excess sFlt1, and will test this notion with genetically modified mice and viral delivery of sFlt1. Success in these studies will provide mechanistic insight into PPCM, a poorly understood disease, and would open novel therapeutic approaches for a disease that currently has no specific treatment.