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

子痫前期(PE)是妊娠20周后出现的新发高血压和蛋白尿，是一种 由胎盘介导的严重妊娠特有疾病，影响所有妊娠的5%。临床部 PE的特征是由弥漫性母体内皮细胞功能障碍引起的，由 母血中循环中的抗血管生成因子(即sFlt1、PlGF)。有过PE经历的女性有 增加了心血管疾病的终生风险。PE的潜在病因仍知之甚少； 因此，预测性和治疗性选择仍然有限，交付是唯一的治愈方法。以另一种形式的 妊娠期急性脂肪肝(AFLP)，胎儿受常染色体影响的比例增加 隐性脂肪酸氧化障碍(LCHAD)(长链3-羟基辅酶A脱氢酶缺乏症) 由HADHA基因突变引起。AFLP可能是由于长链和3-羟基长链的积聚所致。 胎盘中的链状脂肪酸，然后被输送到母体循环中，导致母体 肝脏毒性。基于一种假设，即潜在的代谢变化可能是许多人对PE的倾向的基础 女性，我们最近对来自女性的第一和第二个月的血浆样本进行了全球代谢谱分析 发生早发性PE(EO-PE，分娩37周)的患者和与之匹配的对照组。在这个队列中，EO-PE病例 有证据表明早期线粒体脂肪酸β氧化异常(β-FAO)，以血浆升高为特征 中链和长链脂肪酸、酰肉碱和酮。这些数据表明，功能失调的β-粮农组织 线粒体作为PE发病的早期步骤。在这里，我们提出了一系列实验，以了解 β-fao基因在PE中表达异常的原因及β-fao基因异常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- 妊娠早期胎盘的氧化是PE发病的重要介质。为了测试这一点 假设，我们将：(1)通过检查来描述在PE中产生异常脂肪酸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、基因表达和代谢物 以及(2)β-FAO相关代谢物升高对线粒体的功能影响。 细胞类型在PE发病中起重要作用(即胎盘滋养细胞和母体血管内皮细胞)。一起， 这些目标将确定在发生PE的妇女中β-粮农组织失调的分子基础，并确定 粮农组织相关代谢产物对滋养层细胞和血管内皮细胞线粒体功能的特异性影响。 我们预计这些实验将显著加深我们对PE发病机制的了解，最终导致 改善了PE的预测和治疗选择。另外，我在这个职业生涯中将接受的培训 获奖对我实现发展独立研究项目的长期目标至关重要 基于将患者的综合经济学分析结果转化为功能随访以了解 产科不良结局的潜在机制。

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.