Signatures of dysfunctional mitochondrial fatty acid oxidation that predispose to early-onset preeclampsia

先兆子痫（PE）是妊娠20周后新发高血压和蛋白尿的发展，是一种高血压疾病， 由胎盘介导的严重妊娠特异性疾病，影响所有妊娠的5%。临床 PE的特征是由弥漫性母体内皮细胞功能障碍引起的，由内皮细胞的不平衡介导。 母体血液中循环的抗血管生成因子（即，sFlt1、PlGF）。有PE病史的女性 心血管疾病的终生风险增加。PE的潜在病因仍然知之甚少; 因此，预测和治疗选择仍然有限，交付是唯一的治愈方法。在一种变体形式中， PE，妊娠急性脂肪肝（AFLP），胎儿受常染色体影响的比例增加 隐性脂肪酸氧化障碍（长链3-羟酰辅酶A脱氢酶缺乏症） 是由HADHA基因突变引起的AFLP可能是由于长链和3-羟基长链的积累， 胎盘中的脂肪酸链，然后被运送到母体循环中，导致母体 肝毒性基于以下假设，即潜在的代谢变化可能是许多患者PE倾向的基础， 最近，我们对来自女性的第一和第二孕期血浆样本进行了总体代谢分析， 发生早发性PE（EO-PE，分娩<37周）和匹配的对照组。在该队列中，EO-PE病例 有早期异常线粒体脂肪酸β-氧化（β-FAO）的证据，其特征是血浆 中链和长链脂肪酸、酰基肉毒碱和酮。这些数据表明β-FAO功能失调， 线粒体作为PE发病机制的早期步骤。在这里，我们提出了一系列的实验，以了解 为什么β-FAO在PE中失调，并测试异常β-FAO对线粒体功能的影响， 胎盘和母体血管系统。我们的中心假设是功能失调的线粒体脂肪酸β- 在妊娠早期开始的胎盘中的氧化是PE发病机制的关键介质。为了验证这一 假设，我们将：（1）通过检查PE中异常脂肪酸β-氧化的水平， 母体和胎儿/胎盘妊娠中β-FAO相关的遗传变异、基因表达和代谢产物 样品，和（2）表征升高的β-FAO相关代谢物对线粒体的功能影响， PE发病机制中不可或缺的细胞类型（即，胎盘滋养层和母体血管内皮）。在一起， 这些目标将确定发生PE的女性中β-FAO失调的分子基础，并确定 FAO相关代谢物对滋养层细胞和血管内皮细胞线粒体功能的特定影响。 我们预计这些实验将大大加深我们对PE发病机制的认识，最终导致 改善PE的预测和治疗选择。此外，我将在这一职业生涯中接受的培训 一个奖项将是必不可少的，我实现我的长期目标，发展一个独立的研究计划 基于将患者的综合`组学分析结果转化为功能随访， 不良产科结局的潜在机制。

Preeclampsia (PE), the development of new-onset hypertension and proteinuria after 20 weeks gestation, is a severe pregnancy-specific disorder mediated by the placenta that affects 5% of all pregnancies. The clinical features of PE are caused by diffuse maternal endothelial cell dysfunction, mediated by an imbalance of circulating anti-angiogenic factors in the maternal blood (i.e., sFlt1, PlGF). Women with prior PE have an increased lifetime risk of cardiovascular disease. The underlying etiology of PE remains poorly understood; consequently, predictive and therapeutic options remain limited and delivery is the only cure. In a variant form of PE, acute fatty liver of pregnancy (AFLP), an increased proportion of fetuses are affected by the autosomal recessive fatty acid oxidation disorder, LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency) caused by mutations in the HADHA gene. AFLP may result from the build-up of long-chain and 3-hydroxy long- chain fatty acids in the placenta, which are then transported into the maternal circulation and lead to maternal liver toxicity. Based on the hypothesis that underlying metabolic changes may underlie disposition to PE in many women, we recently performed global metabolic profiling on 1st and 2nd trimester plasma samples from women who developed early-onset PE (EO-PE, delivered <37 weeks) and matched controls. In this cohort, EO-PE cases had evidence of early abnormal mitochondrial fatty acid β-oxidation (β-FAO), characterized by increased plasma medium- and long-chain fatty acids, acylcarnitines, and ketones. These data implicate dysfunctional β-FAO by the mitochondria as an early step in PE pathogenesis. Here we propose a series of experiments to understand why β-FAO is dysregulated in PE and test the effects of abnormal β-FAO on mitochondrial function in the placenta and maternal vasculature. Our central hypothesis is that dysfunctional mitochondrial fatty acid β- oxidation in the placenta beginning in early pregnancy is a critical mediator of PE pathogenesis. To test this hypothesis, we will: (1) delineate the level at which abnormal fatty acid β-oxidation originates in PE by examining β-FAO-associated genetic variants, gene expression, and metabolites in maternal and fetal/placental pregnancy samples, and (2) characterize the functional effects of elevated β-FAO-related metabolites on mitochondria in cell types integral in PE pathogenesis (i.e., placental trophoblasts and maternal vascular endothelium). Together, these aims will define the molecular basis for dysregulated β-FAO in women who develop PE and determine the specific effects of FAO-related metabolites on mitochondrial function in trophoblasts and vascular endothelium. We anticipate these experiments will significantly deepen our knowledge of PE pathogenesis, ultimately leading to improved predictive and therapeutic options for PE. Additionally, the training I will receive during this career award will be essential for me to achieve my long-term goal of developing an independent research program based in translating results of integrative `omic analyses in patients into functional follow-up to understand mechanisms underlying adverse obstetric outcomes.