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

线粒体脂肪酸氧化功能失调的特征易患早发性先兆子痫

基本信息

批准号：
10604296
负责人：
Kathryn Johnson Gray
金额：
$ 8.64万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-03 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10604296
关键词：
3-Hydroxyacyl-CoA dehydrogenase Acute Affect Angiogenesis Inhibitors Angiogenic Factor Award Biopsy Blood Blood Coagulation Disorders Blood Platelets Circulation Clinical DNA Data Development Diabetes Mellitus Diagnosis Diffuse Disease Endothelial Cells Enzymes Erythrocytes Etiology Fatty Acids Fatty Liver Fetal Growth Fetus First Pregnancy Trimester Functional disorder Gene Expression Genes Goals HELLP Syndrome Hematology Hemolysis Hepatotoxicity Human Hypertension Hypoglycemia Impairment Ketones Kidney Failure Knowledge Laboratory Study Lead Liver Liver Dysfunction Maternal Mortality Mediating Mediator Metabolic Metabolism Mitochondria Molecular Mothers Mutation Nonesterified Fatty Acids Oxidative Stress PGF gene Pathogenesis Pathway interactions Patients Placenta Plasma Play Pre-Eclampsia Predisposition Pregnancy Pregnancy Complications Premature Birth Production Proteins Proteinuria Public Health RNA Research Respiration Risk Role Sampling Second Pregnancy Trimester Series Subgroup Superoxides Symptoms Syndrome Testing Therapeutic Time Training Translating United States Up-Regulation Variant Vascular Endothelium Woman acylcarnitine adverse pregnancy outcome autosome blood pressure elevation cardiovascular disorder risk career cell growth regulation cell type cohort early onset early pregnancy exome sequencing experimental study fatty acid metabolism fatty acid oxidation fetal follow-up genetic variant improved lifetime risk liquid chromatography mass spectroscopy long chain fatty acid maternal liver dysfunction nano-string normotensive obstetric outcomes oxidation prepregnancy obesity programs screening trophoblast urinary

项目摘要

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.

先兆子痫 (PE) 是妊娠 20 周后新发高血压和蛋白尿的一种疾病。由胎盘介导的严重妊娠特异性疾病，影响所有妊娠的 5%。 PE 的特征是由弥漫性母体内皮细胞功能障碍引起，该功能障碍是由母体血液中存在循环抗血管生成因子（即 sFlt1、PlGF）。心血管疾病的终生风险增加对PE的潜在病因仍知之甚少；因此，预测和治疗选择仍然有限，交付是唯一的治疗方法。 PE，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-羟酰基辅酶A 脱氢酶缺乏症）由 HADHA 基因突变引起的可能是长链和 3-羟基长链的积累造成的。胎盘中的链脂肪酸，然后转运到母体循环中，导致母体肝毒性基于以下假设：潜在的代谢变化可能是许多人患 PE 的原因。女性，我们最近对女性第一和第二个月的血浆样本进行了整体代谢分析发生早发性 PE（EO-PE，分娩<37 周）的患者和匹配的对照组在该队列中为 EO-PE 病例。有早期线粒体脂肪酸β-氧化（β-FAO）异常的证据，其特征是血浆增加这些数据表明 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实验来了解。为什么 β-FAO 在 PE 中失调，并测试异常 β-FAO 对 PE 中线粒体功能的影响我们的中心假设是线粒体脂肪酸β-功能失调。妊娠早期开始的胎盘氧化是 PE 发病机制的关键介质。假设，我们将：（1）通过检查来描述 PE 中异常脂肪酸 β-氧化的起源水平母体和胎儿/胎盘妊娠中与 β-FAO 相关的遗传变异、基因表达和代谢物样品，(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细胞）。这些目标将确定患有 PE 的女性中 β-FAO 失调的分子基础，并确定与FAO相关的代谢物对滋养层和血管内皮线粒体功能的具体影响。我们预计这些实验将显着加深我们对 PE 发病机制的了解，最终导致此外，我将在职业生涯中接受培训，以改善PE的预测和治疗选择。该奖项对于我实现开发独立研究项目的长期目标至关重要基于将患者的综合“组学分析”结果转化为功能性随访，以了解不良产科结局的潜在机制。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute Fatty Liver of Pregnancy: Pathophysiology, Anesthetic Implications, and Obstetrical Management.

妊娠期急性脂肪肝：病理生理学、麻醉影响和产科管理。

DOI：
发表时间：
2019
期刊：
影响因子：
8.8
作者：
Naoum, Emily E;Leffert, Lisa R;Chitilian, Hovig V;Gray, Kathryn J;Bateman, Brian T
通讯作者：
Bateman, Brian T

Hemodynamic changes in patients with SARS-CoV-2 infection presenting for cesarean delivery under spinal anesthesia: a retrospective case-control study.

脊髓麻醉下剖宫产的 SARS-CoV-2 感染患者的血流动力学变化：一项回顾性病例对照研究。

DOI：
发表时间：
2023-02
期刊：
影响因子：
2.8
作者：
Scoon, L E G;Gray, K J;Zhou, G;Cohen, R Y;Armero, W;Chen, Y K;Ray, A M;Diouf, K;Goldfarb, I T;Boatin, A A;Kovacheva, V P
通讯作者：
Kovacheva, V P

Prediction of Preeclampsia from Clinical and Genetic Risk Factors in Early and Late Pregnancy Using Machine Learning and Polygenic Risk Scores.

使用机器学习和多基因风险评分从妊娠早期和晚期的临床和遗传风险因素预测先兆子痫。

DOI：
发表时间：
2023-02-07
期刊：
影响因子：
0
作者：
Kovacheva, Vesela P;Eberhard, Braden W;Cohen, Raphael Y;Maher, Matthew;Saxena, Richa;Gray, Kathryn J
通讯作者：
Gray, Kathryn J

Tolerance of uncertainty: a unifying theme in pregnancy care.

对不确定性的容忍：妊娠护理的统一主题。