Sirt1-PPARgamma signaling in placental development and fetal growth disorders

描述（由申请方提供）：胎儿生长障碍（生长受限和过度生长）是常见的妊娠并发症，会增加围产期不良结局的风险，并增加成人疾病（包括糖尿病和心血管疾病）的风险。胎盘是一个胎儿衍生的器官，其正常发育和功能是怀孕成功的关键。滋养层细胞构成胎盘的上皮区室，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形成早期滋养层分化和功能障碍有关，导致慢性胎儿-胎盘缺氧。PPARgamma是一种配体激活的转录因子，也是噻唑烷二酮家族抗糖尿病药物的靶点，Sirt 1是一种蛋白质脱乙酰酶，也是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、营养感应和代谢。我们已经表明，Sirt 1-PPARgamma信号是专门参与滋养细胞分化和缺氧诱导的滋养细胞损伤。此外，Sirt 1基因敲除和PPARgamma过度刺激均显示可导致小鼠胎儿生长受限。最后，在人胎盘中，PPARgamma及其内源性配体的表达和/或活性在与异常胎儿生长相关的胎盘中改变，所述异常胎儿生长包括胎儿生长受限、先兆子痫和妊娠糖尿病。本研究的目的是确定Sirt 1-PPARgamma信号通路在滋养层细胞分化、缺氧诱导的胎盘损伤和胎盘相关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目标，从而降低围产期发病率和死亡率。 公共卫生相关性：胎儿生长障碍，包括生长受限和巨大儿，是常见的妊娠并发症，增加了围产期不良后果的风险，并增加了成人疾病，包括糖尿病和心血管疾病的风险。该项目探讨了胎盘中一种特定信号通路促进胎儿生长的机制，重点是可能改善胎儿健康的潜在治疗靶点。!

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. PUBLIC HEALTH RELEVANCE: Fetal growth disorders, including growth restriction and macrosomia, are common pregnancy complications, which carry an increased risk of adverse outcomes in the perinatal period and development of adult disease, including diabetes and cardiovascular disease. This project explores mechanisms by which one particular signaling pathway in the placenta contributes to fetal growth, focusing on potential therapeutic targets which could improve fetal well-being. !