sFlt and Metabolic Mechanisms of Peripartium Cardiomyopathy

 描述(申请人提供)：围产期心肌病(PPCM)的特点是妊娠晚期或分娩后不久的妇女心脏收缩功能丧失。PPCM影响全球约1/1000的新生儿，并经常导致慢性心力衰竭、需要心脏移植或死亡。因此，这种疾病可能会对原本健康的年轻女性及其新家庭造成毁灭性的影响。人们对PPCM背后的机制知之甚少。我们最近提出了一种新的概念，即PPCM是一种血管疾病，由妊娠晚期胎盘分泌的强大的抗血管因子引发。在这些因素中，最值得注意的是sFlt1，一种可溶性诱骗受体和血管内皮生长因子抑制物。我们建议在PPCM的小鼠模型中通过抑制妊娠期间sFlt1的分泌来正式检验这一假说。我们还建议深入研究sFlt1引起心肌病的机制。我们假设sFlt1通过VEGFR2和VEGFR1中和血管内皮生长因子信号，从而分别对心脏血管密度和营养流量产生不利影响。这一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，我们最近的人类基因数据表明，许多患有PPCM的女性携带着肌动蛋白(一种大型肌瘤蛋白)的突变。我们假设，这些突变容易在怀孕期间导致血管/代谢崩溃，并暴露在过量的sFlt1中，并将在转基因小鼠和sFlt1的病毒传递中测试这一概念。这些研究的成功将提供对PPCM这一鲜为人知的疾病的机械性洞察，并将为目前尚无特定治疗方法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.