Rubicon: a novel target of sex-specific placental dysfunction in maternal obesity

项目摘要 在美国，超过65%的怀孕妇女超重或肥胖。妊娠期肥胖 易使后代肥胖，心血管和代谢紊乱，从而引发“恶性” 肥胖及其对后代健康相关后果的“周期”，即使没有进一步的 子宫内应激源肥胖症、心血管疾病和代谢疾病在世界范围内的流行， 因此，这不仅是久坐不动的生活方式或不良饮食的结果;它也是一个后果， “发育程序”由于子宫内的不利环境而启动。没有 预防发育编程的治疗策略是我们缺乏知识的结果， 母亲肥胖影响后代健康的机制。胎盘是至关重要的 肥胖是胎儿健康生长和发育的决定因素，但肥胖对胎盘健康的后果是 现在才刚刚开始。我们实验室的数据显示， 女性胎儿胎盘中的TNFα与促炎转录激活有关 核因子κ B（NFκB）。炎症受到自噬的严格控制，自噬是一种细胞循环 过程，未解决的炎症与自噬的破坏有关，反过来， 导致心血管和代谢疾病。我们最近的数据表明，男性和女性的胎盘 来自肥胖妇女的雌性后代显示出自噬的抑制。然而，有显着的性别 机制上的差异。在男性胎盘中，自噬的抑制与 在关键的自噬协调转录因子EB。相反，在雌性胎盘中， 自噬通过Rubicon（RUN结构域和含有Beclin 1- 相互作用蛋白），一种新发现的自噬负调节因子。我们发现卢比孔河的水位上升 在肥胖女性的胎盘中，Beclin 1的表达和Beclin 1的结合没有观察到这种现象。 男性的胎盘。我们的数据表明，这些过程至少部分是由TNFα诱导的， 炎症在此，我们假设，作为对母体肥胖在子宫内产生的炎症的反应， 胎盘Rubicon表达的增加引起其蛋白质-蛋白质相互作用的变化， 抑制胎盘自噬。我们将通过三个具体目标来解决这个假设：1）。识别 调控Rubicon表达及其与Beclin 1结合的机制 母亲肥胖2）。确定Rubicon与抑制自噬相关的分子基础， 胎盘肥胖。3）。确定调节胎盘中Rubicon信号传导的性别依赖性机制 母亲肥胖症这项研究将提供机械的见解，将系统和严格地填补 这些差距，从而打开了机会，为发展的Rubicon为基础的疗法，以解决 产妇肥胖对后代的不利后果，这是一个主要的未得到满足的公共卫生需求。

PROJECT SUMMARY More than 65% of women entering pregnancy in the US are overweight or obese. Obesity in pregnancy predisposes the offspring to obesity, and cardiovascular and metabolic disorders, thus initiating a “vicious cycle” of obesity and its health-related consequences in subsequent generations even in the absence of further intrauterine stressors. The worldwide epidemic of obesity and cardiovascular and metabolic diseases, therefore, is not only a result of the sedentary lifestyle or poor diet; it is also a consequence of a “developmental program” switched on as a result of an adverse in utero environment. The absence of therapeutic strategies to prevent developmental programming is a consequence of our lack of knowledge of the mechanisms whereby maternal obesity affects the health of future generations. The placenta is a crucial determinant of healthy fetal growth and development, but the consequences of obesity for placental health are only now beginning revealed. Data from our laboratory have shown an accumulation of inflammatory cytokine TNFα in the placentas of female fetuses is associated with an activation of pro-inflammatory transcription factor nuclear factor κappa B (NFκB). Inflammation is tightly regulated by autophagy, a cellular recycling process, and unresolved inflammation has been associated with a disruption of autophagy, which, in turn, leads to cardiovascular and metabolic diseases. Our recent data suggest that placentas of both male and female offspring from obese women show inhibition of autophagy. However, there are significant sex differences in the mechanisms. In the placentas of males, inhibition of autophagy is associated with a decrease in critical autophagy coordinating transcription factor EB. In the placentas of females, in contrast, inhibition of autophagy is linked to inflammation via Rubicon (RUN domain and cysteine-rich domain containing Beclin1- interacting protein), a newly identified negative regulator of autophagy. We found an increase in Rubicon expression and Beclin 1 binding in the placentas of females of obese women with this phenomenon not seen in placentas of males. Our data suggest that these processes are, at least in part, regulated by TNFα-induced inflammation. Here we hypothesize that in response to inflammation generated in utero by maternal obesity, an increase in placental Rubicon expression occurs causing changes in its protein-protein interaction and thereby inhibiting placental autophagy. We will address this hypothesis with three specific aims: 1). Identify the mechanisms that regulate expression of Rubicon and its binding to Beclin1 in the human placenta with maternal obesity. 2). Determine the molecular basis relating Rubicon to the inhibition of autophagy in the placenta with obesity. 3). Identify sex-dependent mechanisms that regulate Rubicon signaling in the placenta with maternal obesity. This study will provide mechanistic insights that will systematically and rigorously fill these gaps and thereby open the opportunity for the development of Rubicon-based therapies to address the adverse consequences of maternal obesity for offspring, a major unmet public health need.