Sirt1-PPARgamma signaling in placental development and fetal growth disorders

描述（由申请人提供）：胎儿生长障碍（生长受限和过度生长）是常见的妊娠并发症，在围产期会增加不良后果的风险，并增加成人疾病的风险，包括糖尿病和心血管疾病。胎盘是胎儿来源的器官，其正常发育和功能对妊娠成功至关重要。滋养细胞包括胎盘的上皮细胞室，并介导营养/气体交换功能和母体血流进入胎儿-胎盘单位的建立。胎儿生长异常与胎盘早期滋养细胞分化和功能紊乱有关，从而导致慢性胎胎盘缺氧。PPARgamma是一种配体激活的转录因子，也是抗糖尿病药物噻唑烷二酮家族的靶标，而Sirt1是一种蛋白质去乙酰化酶，是PPARgamma的负调节因子，此前已被证明参与细胞和组织功能的多个方面，包括分化、营养感知和代谢。我们已经证明Sirt1-PPARgamma信号通路特异性参与滋养细胞分化和缺氧诱导的滋养细胞损伤。此外，sirt1敲除和PPARgamma过度刺激均可导致小鼠胎儿生长受限。最后，在人类胎盘中，pppargamma及其内源性配体的表达和/或活性在胎盘中发生改变，与胎儿生长异常有关，包括胎儿生长受限、先兆子痫和妊娠糖尿病。本研究的目的是确定Sirt1-PPARgamma信号在滋养细胞分化、缺氧诱导的胎盘损伤和基于胎盘的胎儿生长障碍中的作用机制。该项目有可能确定这些疾病的治疗靶点，从而降低围产期发病率和死亡率。

DESCRIPTION (provided by applicant): Fetal growth disorders (both growth restriction and overgrowth) are common pregnancy complications, which carry an increased risk of adverse outcomes in the perinatal period and an increased risk of development of adult disease, including diabetes and cardiovascular disease. The placenta is a fetal-derived organ, whose proper development and function are pivotal in pregnancy success. Trophoblastic cells comprise the epithelial compartment of the placenta, and mediate nutrient/gas exchange functions and establishment of maternal blood flow into the feto-placental unit. Abnormal fetal growth has been associated with disorders of trophoblastic differentiation and function during early events in placentation, which lead to chronic feto-placental hypoxia. PPARgamma, a ligand-activated transcription factor and target of the thiazolidinedione family of anti-diabetic drugs, and Sirt1, a protein deacetylase and negative regulator of PPARgamma, have previously been shown to be involved in multiple facets of cell and tissue function, including differentiation nutrient-sensing, and metabolism. We have shown that Sirt1-PPARgamma signaling is specifically involved in trophoblast differentiation and hypoxia-induced trophoblast injury. In addition, both Sirt1-knockout and PPARgamma overstimulation have been shown to cause fetal growth restriction in mice. Finally, in human placentas, the expression and/or activity of PPARgamma and its endogenous ligands are altered in placentas associated with abnormal fetal growth, including fetal growth restriction, preeclampsia, and gestational diabetes. The goal of this proposal is to determine the mechanisms by which Sirt1-PPARgamma signaling contribute to trophoblastic differentiation, hypoxia-induced placental injury, and placenta-based fetal growth disorders. This project has the potential to identify therapeutic targets for these diseases, leading to a decrease in perinatal morbidity and mortality.