sFlt and Metabolic Mechanisms of Peripartium Cardiomyopathy

围产期心肌病的 sFlt 和代谢机制

基本信息

批准号：
9338286
负责人：
Zoltan P Arany
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9338286
关键词：
Affect Angiogenic Factor Antibodies Biological Assay Birth Blood Vessels Cardiac Cardiac Myocytes Cardiomyopathies Cell Culture Techniques Cells Cessation of life Collaborations Congestive Heart Failure Data Development Dilated Cardiomyopathy Disease Endothelium Event Exposure to Family Fatty Acids Functional disorder Genes Genetic Genetic Models Heart Heart failure Hormonal Human Human Genetics KDR gene Knock-out Lead Live Birth Measures Metabolic Metabolism Modeling Modernization Molecular Morbidity - disease rate Mus Mutation Myocardium Nature Neutralization Tests Nutrient Oxygen Pathway interactions Perinatal Placenta Pregnancy Pregnant Women Preparation Proteins Publishing Role Sarcomeres Signal Transduction Skeletal Muscle Small Interfering RNA Testing Therapeutic Time Toxic effect Transplantation Tyrosine Kinase Domain United States National Institutes of Health Ursidae Family VEGFA gene Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vegf Inhibitor Viral Woman Work angiogenesis base connectin density experimental study heart metabolism imaging modality in vivo insight mortality mouse model negative affect novel novel therapeutic intervention peripartum cardiomyopathy public health relevance receptor success vascular factor young woman

项目摘要

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.

描述（由适用提供）：腹膜心肌病（PPCM）以怀孕后期或分娩后不久的女性心脏收缩功能的丧失为特征。 PPCM在全球范围内影响大约1：1000个出生，并且经常导致慢性心力衰竭，需要心脏移植或死亡。因此，这种疾病可能会破坏其他健康的年轻妇女及其新家庭。 PPCM的基础机制知之甚少。我们最近提出了一种新颖的观念，即PPCM是一种血管疾病，是由妊娠后期斑点的潜在抗血管因子的分泌引发的。这些因素中最值得注意的是SFLT1，一种可溶性诱饵受体和VEGF抑制剂。我们在这里建议通过在PPCM的鼠模型中抑制妊娠期间的SFLT1分泌正式检验该假设。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VEGF信号传导，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的小鼠模型，细胞培养实验以及心脏代谢的最新测定和成像方式进行检验。最后，我们最近的人类遗传数据指标表明，许多具有PPCM熊突变的妇女是大型肉瘤蛋白。我们假设这些突变在怀孕期间易于血管/代谢崩溃，并暴露于过量的SFLT1，并将通过一般修饰的小鼠和SFLT1的病毒递送来测试这一概念。这些研究的成功将提供对PPCM的机械洞察力，PPCM是一种知名度知之甚少的疾病，并将为目前没有特定治疗的疾病打开新型的治疗方法。